Eur Rev Med Pharmacol Pathogenesis of Atopic Dermatitis ... · Atopic dermatitis, Children, Skin...

cells, T lymphocytes, LC expressing E-cad-herin2, keratinocytes, high endothelial venul-es (HEV), and several adhesion molecules3.Those cells together with eosinophils arestrictly linked to organize the allergic sensiti-zation. Contrary to general findings stressingthat the normal skin contains ª 8.000 mastcells/mm3, Irani et al.4 have demonstratedthat in AD they are ª 20.000-40.000/mm3, and94% are TC (tryptase and chymase). Mastcells participate in the IgE-mediated hy-persensitivity reactions, and have been identi-fied in the epidermis of AD patients5. Mastcells of the human skin, but not those of oth-er tissues, have been found to be able tomount a secretory response (histamine andother mediators) to a host of non immuno-logical stimuli, such as neuropeptides, includ-ing substance P (SP), vasoactive intestinalpeptide (VIP), somatostatine, etc.6, but not toeosinophil granule proteins, two of which,MBP (major basic protein) and EPO(eosinophil peroxidase), inhibit SP-inducedhistamine release from human skin mastcells7. Dermal mast cells contain and releaseIL, among which TNF-α (tumor necrosis fac-tor-α)8,9 which induces endothelial leukocyteadhesion molecule 1 (CD62E) due to cross-linking with the high-affinity receptor for IgE(FcεRI)9. The direct activation of mast cellsby IgE and the interactions also independentof CD40, and CD40L, which is expressed byboth metachromatic cells, become apparentwith the potential induction of IL4, a clearexplanation of the amplification and propa-gation of Th2-response10. This findingdemonstrates that IgE-sensitization is a clear-cut reality.

Immunohistochemical staining of acute andchronic skin lesions in AD reveal a scarcenumber of infiltrating lymphocytes which con-sist predominantly of T cells (CD3, CD4,

European Review for Medical and Pharmacological Sciences

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Abstract. – Objective. In this paper we willdemonstrate that the exact pathogenesis of atopicdermatitis (AD) remains enigmatic, however thecentral defect is genetically determined, and theseveral dysfunctions we will highlight all point to avicious cycle of allergen exposure, allergen-spe-cific IgE production, and chronic Th2 cell stimula-tion. An important role is played by the late phaseof IgE-mediated hypersensitivity, and evidence isaccumulating that eosinophils actively participatein late phase-allergic reactions also in the skin.

Observations. AD is the first atopic disease toappear in the absolute sense: dendritic cells (DC)develop firstly in the skin and then in lung, in addi-tion to homing receptors for T lymphocytes thatare selective for skin localizations and not forlung. Among the DC, a primary role is reserved toLangerhans cells (LC) that express E-cadherin, ahomophilic adhesion molecule that is prominentlyrepresented in epithelia. In addition keratinocytesand the interleukins (IL) they express are capableof activating a host of IgE-bearing cells.

Conclusion. Although much new informationregarding the pathogenesis of AD has evolvedover the past several years, the basic underlyingetiology of this disorder remains elusive.Preventive measures are the only treatment forAD. We hope that the coming years will witnessthe development of new strategies for the treat-ment of AD, aimed at specific targets based on athorough understanding of its pathogenesis.

Key Words:

Atopic dermatitis, Children, Skin immune system, Tcells, IgE antibodies, Langerhans cells, Preventivemeasures.

Opening the Scenario:the Cells Orchestrating

Cutaneous Inflammation

The principal cellular constituents of skinimmune system (SIS)1 are as follows: mast

Pathogenesis of Atopic Dermatitis (AD)and the role of allergic factors

A. CANTANI

Division of Allergy and Clinical Immunology, Department of Pediatrics, “La Sapienza" University - Rome (Italy)

2001; 5: 95-117

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CD45RO) and HLA-DR surface antigenswith only occasional CD8+ lymphocytes11. Itis tempting to speculate that the several im-munologic and perhaps functional similaritiesbetween the thymic epithelium and the epi-dermis may explain the potential role of skinin the maturation of specific subpopulationsof lymphocytes: even if the SIS lymphocytesexpress the two phenotypes, B and T, thegreat majority of cells locally present are Tlymphocytes and perhaps no additional affec-tion is associated with an exclusive infiltrationof T cells12. In contrast, B cells are virtuallyabsent13. In addition, there are recirculatingmemory cells (CD45RO+)14, all with CLA(cutaneous lymphocyte-associated antigen),expressed by 45% of skin T cells15. The CD45are activated, thus suggesting a previous con-tact with allergens, since virgin T cells localizepoorly in skin16. Other studies have providedcrucial data regarding vascular endothelialcells expressing high concentrations of skin-homing memory cells such as CD62E, CD54(ICAM-1), and CD106 (VCAM-1)16,17, withthe HEV also expressing CD62E18. CD62Eserves as a major skin-specific addressin insites of chronic inflammation and interactswith CLA18. Additional counterreceptors onlymphocytes are α4fl1 = CD49d/CD29 forCD106 and CD11a = LFA-1 for CD5416. Inthe multistep paradigm18, MCP-1 (monocytechemotactic protein-1) is an additional im-portant chemoattractant for T cells, and inthis specific case is the receptor associated toGa1 proteins, whereas CD49d/CD29 andCD11a/CD18 link respectively CD106 andCD54/102 (ICAM-2)18. Therefore adhesionmolecules specific for the skin compartmentbind preferentially T CLA+ (or MCP-1+)cells, thus favoring their accumulation in theskin chronic lesions, while the regional lymphnodes draining secondary lymphoid tissueslink the cutaneous compartments with bloodthrough afferent and efferent pathways3,19. Inparticular, TNF-α18,19 has the capacity to actfor selective subpopulations of circulating Tcells, especially CD4+CD45RO+ expressingCLA or MCP-1 favoring T cells homing inskin, and their adhesion to endothelium15. Theconclusion is that all these molecules favorCLA localization specifically in skin sites,while CLA negative is represented in lung tis-sues20, therefore the lymphocyte T subsets arethe inducers of atopic dysregulation firstly in

skin tissues, and secondly in lung, thus paral-leling the LC absence in lung in the firstmoths of life21.

Keratinocytes make up about 95% of theepidermal cells, and represent the main cuta-neous cells releasing ILs. They may act as sig-nal transducers, capable of converting ex-ogenous stimuli, such as local injuries, me-chanical irritations, UV radiations, into theproduction of epidermal proinflammatoryILs, integrins and chemotactic factors, as wellas LCs, and as a consequence may initiateand exacerbate cutaneous inflammation22,23.The first cells to encounter the allergens, arenow believed to play an active part in init-iating and perhaps directing the mucosal im-mune response22 by the release of variousILs23. Keratinocytes exert an active immun-oregulatory role in concert with infiltratingperipheral blood mononuclear cells (PBMC);they aberrantly express class II HLA-DRantigens and CD54, correlated with lympho-cyte infiltration, CD36 antigen22, and cutan-eous platelet-derived growth factor(PDGF)24, in addition to releasing adhesionmolecules. Skin keratinocytes do not normal-ly express the HLA-DR antigens, but can beinduced to do so in the presence of activatedT lymphocytes in correspondence of primarysensitization. However, the lack of HLA-DRexpression by keratinocytes may play a rolein the induction of the T-cell stimulation lead-ing to the differentiation of allergen-specificTh2 lymphocytes and the development of al-lergy25. Further studies will elucidate whetherthe Th2 differentiation precedes the lack ofHLA-DR induction, or alternatively the lackof HLA-DR is the primary factor leading toTh2 activation25. On the contrary epidermalkeratinocytes constitutively expressing CD80can be transformed into efficient APC (anti-gen presenting cells), and play an importantrole in the resolution of DTH (delayed-typehypersensitivity) reactions in the skin basedon their ability to induce T-helper cell clonalanergy26. Altered regulation of CD80 geneexpression by epidermal cells may accountfor skin “hyperresponsiveness” encounteredin chronic AD26.

Recent studies indicate a role foreosinophil disruption and degranulation inmodulating tissue destruction27. CD40 ligand(CD154) is functionally expressed on humaneosinophils28, thus promoting the shifting of

A. Cantani

B lymphocytes to the IgE phenotype.Eosinophils are not only active in mediatingallergic inflammation, but intervene in cellu-lar networks with APCs, mast cells, and Tlymphocytes29. Several potent, toxic andcationic proteins, have been observed in theeosinophil granules, including MBP,eosinophil-derived neurotoxin (EDN),eosinophil cationic protein (ECP), and EPO.It was found that these proteins are implicat-ed in tissue damage associated with skin in-flammation however their role in the patho-physiology of AD is still unclear27,29.

It was shown that some of these proteinsare elevated in the peripheral blood of pa-tients with AD27. Usually, serum levels ofMBP are elevated in patients affected by var-ious disorders associated with eosinophiliaand correlate significantly with the number ofperipheral blood eosinophils30. ECP andMBP levels are low in serum and/or in theskin of healthy subjects, and high in those af-fected (MBP 454 ± 90 versus 687 ± 299ng/ml)31,32. However, both increased levels ofMBP in the peripheral blood and peripheralactivation of eosinophils have been demon-strated. Although peripheral bloodeosinophilia is a common feature of AD, ac-cumulation of tissue eosinophils is not promi-nent33. Several studies have shown eosinophildisruption and loss of morphological identityin the skin of patients with AD32-34. More rec-ently, it has been studied the eosinophil de-granulation in human skin tissues. Immu-nofluorescent staining of the affected skindemonstrated extensive deposition of MBCin the absence of many tissue eosinophils sug-gesting that such cells degranulate in the skin.In more than half of AD specimens exam-ined, Leiferman et al. also found MBP depo-sition in a granular pattern deeper in the der-mis. Extracellular MBP deposition was muchmore diffuse in the involved areas than in theuninvolved areas of the skin34. Interestingly,extensive MBP deposition in the skin wasdemonstrated in 2 children who experiencedeczematous lesions after DBPCFC (double-blind, placebo-controlled food challenge),thus indicating again the role of food allergy(FA) and eosinophils in AD34.

EDN deposition was studied by Leifermanin patients with AD27. AD skin specimensshowed extensive granular extracellular EDNdeposition in the upper dermis, thus pro-

ducing further evidence for EDN role in AD.Electron microscopy examination showedeosinophil degeneration and disruption withmany free granules in the dermis, thus cor-roborating the evidence of eosinophil degran-ulation in AD27. In addition, this study seemsto indicate that peripheral blood EDN maybe a more sensitive marker of eosinophil de-granulation than peripheral blood MBP27.

According to other authors, elevatedserum levels of ECP in children with ADwere found35. Serum levels of ECP were 12.2mg/l ± 9.6 in children with AD, and 6.6 mg/l ±3.7 in normal children (p < 0.001). Despitethe absence of correlation between ECPserum levels and total IgE as well as betweenthe absolute number of peripheral bloodeosinophils and ECP serum levels35, it seemslikely that elevated ECP serum concen-trations in patients with AD may reflect theeosinophil activation in the skin. However ithas been reported that in vitro ECP can in-duce an increased histamine release36 and cansuppress T-lymphocytes function via a non-toxic mechanism37. It is therefore tempting tospeculate that eosinophil cationic proteins, inaddition to noxious effects for the skin, maycontribute to the profound immunologic ab-normalities described in patients with AD.The detection of ECP levels raised in serumof AD patients and correlated with diseaseseverity38 represents only an indirect measureof the pathological process taking place in theskin. Therefore ECP measurement may rep-resent a non invasive tool to assess the clini-cal activity of AD in relation to eosinophil in-volvement in AD35,38.

LC and macrophagesLC = CD1a+ (3-4%), the epidermal con-

tingent belonging to the family of potentaccessory cells termed DC, act as APC, ex-press HLA class II antigens, and CD1a andCD4 antigens39,40. The function of the cyto-plasm granules of Birbeck is as yet poorlyknown41. LC located in the suprabasal layerof epidermidis express E-cadherin, the ho-mophilic adhesion molecule that mediatestheir adhesion to keratinocytes in vitro2. LCexpress also CD11a, CD11b, CD36 andHLA-DR in chronic lesions, at variance withnormal skin42,43, and in addition CD5444,CD80 and CD8645. A major breakthrough inour understanding of AD pathogenesis oc-

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Pathogenesis of Atopic Dermatitis (AD) and the role of allergic factors

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curred with the demonstration of membrane-bound IgE on epidermal LC42,46. Studies withCD1+ have demonstrated that LC in ADbind both FceRI and FceRII = CD2346, indifferent proportions: 6,63 ± 1,92 versus 0,67± 1,12 cells, respectively47, an upregulation ofFceRI not present in allergic contacteczema48. However the functional role forCD23 should not be undervalued, since itsexpression is upregulated by IL4

15. In additiona facilitated antigen processing throughCD23 has been found. Specific T-cellresponses could be detected using 1000-foldlower levels of serum IgE complexed aller-gens in a CD23-dependent system49. Muddeet al.50 have shown that IgE+ LC but not IgE-LC were capable of presenting Der p al-lergens to T cells, thus suggesting that cell-bound IgE on LC may facilitate binding of al-lergens to LCs prior to their processing andpresentation. As a consequence, the ex-pression of IgE-bearing LC in AD may haveserious pathogenetic outcomes.

Macrophages infiltrating into the AD skinlesions have been shown to bear CD23 ontheir cell surfaces51 expressed in response toIL4

52 or GM-CSF53, and are recruited bymonocyte chemotactic protein-3 (MCP-3)and RANTES (regulated on activation nor-mal T expressed and secreted) in the skin ofhuman atopic subjects54. It has also beendemonstrated that allergens activate IgE-bearing macrophages in an IgE-dependentmanner, with formation of leukotrienes, PAF(platelet activating factor), IL1, and TNF55,56.IgE-bearing macrophages may also been acti-vated by autoantibodies to IgE, which can bepresent in patients with AD57. Taken togeth-er, these data suggest that although IgE-bear-ing LC and macrophages can be found in oth-er inflammatory skin conditions, such as pso-riasis, these skin diseases are not associatedwith the production of allergen-specificIgE13,42.

LC as APC and T lymphocytesLC are the most potent cells in the epider-

mis as regards the presentation of allergens.The presentation of inhalant allergens in pa-tients with AD can be facilitated by the bind-ing of allergen to LC-bound IgE. After con-tact with allergen, some LC become acti-vated, exit the epidermis, thus the LC-boundallergen is transferred to the dermis, finally

the LC migrate to T-cell-dependent regionsof regional lymph nodes where they localizeas mature LC58-60. LC process protein anti-gens, express high levels of HLA class I andII and present Der p allergen to naive T cells,inducing their activation50,61, and to mastcells, stimulating the release of mediators. Asto the pathogenesis of AD, the lymphocyteactivation must be viewed as the most signifi-cant reaction-sequence62. Without doubt theallergen-specific T cells activated by allergen-IgE+ LC release IL4 and IL5, consequently Blymphocytes in the afferent lymph nodes syn-thesize IgE and the bone marrow formseosinophils. Therefore, high serum IgE levelsand peripheral blood eosinophilia are crucialphenomena in AD related to the stimulationof T cells by IgE-bearing LC after the bindingof allergens41. Since no B cells are found inAD patients42, the T lymphocyte activationmust be translated systemically rather thanlocally, thus explaining the strongly elevatedserum IgE levels and peripheral bloodeosinophilia in such subjects62. The IgE thusformed will provide LC with cell-bound IgE:as a result LC will unremittingly stimulate al-lergen-specific Th2 lymphocytes rather thanmast cells41. It is possible that the forces thatdrive differentiation into Th2 cells in AD pa-tients are related to an abnormality inAPCs15, as recently confirmed by studies onTAP63. Th2 amplification favoring decreasedIFN-γ and the resulting high IL4 productionin AD promote IgE synthesis64.

Cytokines and ADSumming-up the data as yet reviewed on

the role of ILs released by epidermal cells inthe pathogenesis of AD, we show the originsof skin ILs in Table I23,65. TGF-β and IL10

have been identified as inhibitors of severalILs66. In addition TNF-α expressed by mastcells up-regulates CD62E on keratinocytes,

A. Cantani

• LC: IL1, IL6, IL8, IL10, G-CSF, GM-CSF, M-CSF,TNF-α;

• Keratinocytes: IL1, IL3, IL6-IL8, IL10, G-CSF,GM-CSF, M-CSF, PDGF, TGF-α and -β, TNF-α;

• Melanocytes: IL1, IL6, IL8, G-CSF, GM-CSF,M-CSF, PDGF, TGF-α and -β, TNF-α

Table I. Cells producing skin cytokines.

Data from 23, 65.

facilitating their interactions with CD11a/CD18-T cells67. The IL production by T-lym-phocyte clones in AD is summarized in TableII68,69.

The Background: Genetic Factors

The genetic factors form the backgroundof the atopic diathesis of AD which is knownsince 191670. Positive associations with theHLA system have been thoroughly examinedbut not fully established71. To date no definiteconsistent association has been found withHLA-A, -B, -C and -DR antigens72, neitherwith a gene on 11q1373, nor in children withcow milk (CM) allergy (CMA) and in theirparents with alleles HLA-A, HLA-B andHLA-DR, or with alleles of HLA-D domain,such as DQ and DR52/5374. A recent study inchildren with AD and CMA found a positiveassociation with HLA-DQ, and that DQ+children had a prevalence of humoral ratherthan cellular responses75. Additional positiveassociations have been established with DPB,DRB76, HLA-A1 and -B5 in patients withDA, but complicated by asthma and/or aller-gic rhinitis (AR)77. Kuwata et al.63 studied thetransporter (TAP genes) polymorphism asso-ciated with antigen-processing genes in ADand reported a tendency toward an increasedfrequency of TAP-1 637Asp in subjects withAD. This, they concluded, may contribute incombination with DRB1*1302/DQB1*0604to the pathogenesis of AD63. An associationbetween AD and genetic variants of mast-cellchymase (MCC) located on chromosome14q11.2 has been found78. Since there is noassociation of MCC with atopic asthma, AR,

or non-atopic asthma, these findings suggestthat the genetic basis of AD may involve theinteraction of variants of MCC (promotingskin inflammation)78 and FceRIβ on chromo-some 11q (promoting enhanced IgE re-sponses and atopy)79. In severe AD patientswas found an allele for the a subunit of theIL4R that segregates with atopy, thus predisp-osing persons to allergic diseases80. Further,AD patients produce IgE antibodies againstenvironmental allergens regulated by CD4+HLA-class II restricted, although cytotoxicCD8+ HLA-class I restricted subpopulationsmay predominate in the infiltrates in AD le-sions81.

As regards the genetic inheritance82, theavailable evidence suggests that AD is in-herited with an autosomal dominant or re-cessive pattern, always associated with ab-normal IgE production, however the etiologyof this disorder remains enigmatic83. Themode of inheritance is not consistent andmay display autosomal dominant andautosomal recessive patterns, although theautosomal dominant trait has been reportedmore frequently, in association with a mater-nal pattern of transmission73,84. Accordingly,AD is less likely a monogenic disorder withessentially weak penetrance, but the interac-tion of multiple genes and multiple exoge-nous or environmental factors outline amultifactorial inheritance pattern with apolygenic component, which better encom-passes the variety of biochemical and im-mune abnormalities involved in the pheno-typic expression of disease. Nonetheless,bone marrow transplantation experience hasdemonstrated clearing of AD with normal-ization of IgE serum levels in patients withWiskott-Aldrich syndrome (WAS) following

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Table II. Cytokine production by T-lymphocyte clones in AD.

Modified by 68, 69.

Cytokines Dpt-specific CD4+ Atopic donors T-lymphocyte clones non-atopic donors

IL2 + +++IL4 +++ –IL5 +++ +IL6 +++ ++GM-CSF +++ +++IFN-γ + +++TNF-α +++ +++

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successful engraftment85. Conversely, trans-fer of AD, and latent atopy, and antigen-spe-cific IgE has also been observed after suc-cessful reconstitution with atopic donor bonemarrow86. As Sampson points out13, taken to-gether these reports suggest that a genetical-ly inherited bone marrow-derived cell is cen-tral to the immunopathogenesis of AD.

The role of atopic heredity in the develop-ment of AD is well established, and is a sig-nificant risk factor (OR > 1)82. In monozygot-ic (MZ) twins the pairwise concordance rateis 0.72 versus 0.23 in dizygotic (DZ) pairs72,and in MZ boys is 0,54 versus 0.35 of DZ boyswhile for girls is 0.73 (MZ) versus 0,40(DZ)87. Twin studies also demonstrate thatoffsprings of parents who had AD are at high-er risk for AD than even those with parentshaving other atopic disease72. Genetic effectsmay account for 33-76% of the variation in li-ability to atopic diseases, however twin girlshave a higher risk of being diagnosed withAD than boys87. Regarding the risk factors inthe progeny, parental AD significantly increa-ses the risk of early development of AD (OR2,5-3,4), compared with children withparental asthma or AR (OR 1,4-1,5)82. In ad-dition, when both parents have atopic diseaseof the same sort, the risk of atopic disease intheir child is 80%; if parents have differentatopic disease the child has a risk of 61% ofdeveloping a similar phenotype, and whenonly one parent is atopic the risk at 2 years is38%88,89. Available evidences call attention toa possible parallel between AD and T-cellPID (primary immune deficiencies) charac-terized by high IgE levels, thus leading to theproposal that AD might fit a pattern ofPID85,90. However such an assumption can berejected since clinically in patients with ADno firm evidence for systemic immunosup-pression has been consistently put forward15,in addition the analysis reveals that AD itselfis not a manifestation of decreased CMI (cellmediated immunity), neither it is precipitatedby an increased susceptibility to generalizedinfections91. However, the prevalence of se-vere skin infections, bacterial, viral and possi-bly by fungi and yeasts15, as well as the de-creased responsiveness to contact allergens92,the cutaneous anergy to skin prick tests (SPT)with several antigens, and a reduceddinitrochlorobenzene sensitization42, point toan abnormal regulation of SIS90.

In AD children several immunologic ab-normalities (Table III)15,42 have been foundwhich can be regarded as the result of de-creased activity of cyclic nucleotides, such asreduced T-suppressor activity, exaggeratedIgE concentrations, increase of cyclic-AMPPDE (phosphodiesterase) activity, abnormalcutaneous permeability barrier, where abno-rmalities of EFA (essential fatty acids)metabolism may explain the dry skin and theincrease in trans-epidermal water loss charac-teristic of AD93 (biochemical abnormalities).

Implications for thePathogenesis of AD

Immune abnormalitiesSeveral lines of evidence suggest that a va-

riety of qualitative and/or quantitative im-

A. Cantani

Table III. Genetic-immunologic and clinical features ofAD.

Adapted from 15, 42.

Genetic-immunologic

Genetic background of atopic syndromeIncreased levels of allergen-specific IgE in serum

and skinNormal serum IgA, IgG and IgM concentrations Preferential expression of allergen-specific Th2

lymphocytesDecreased CD8 suppressor/cytotoxic number and

functionIncreased expansion on CD23 on B and mononu-

clear cells (PBMC)Increased production of IL4/IL5/IL10 and other Th2-

like ILDecreased levels of IFN-γ/IL12/IL18 and other Th1-

like ILDeficit of PBMC not secreting IFN-γ/IL12

Increased basophil releasabilityPersistent macrophages activation with hypersecre-

tion of GM-CSF, PGE2, IL10

Autonomic nervous system dysregulationDisturbed essential fatty acid metabolismRole of foods and food additivesRole of aeroallergensRole of infections ClinicalTypical flexural localization of skin lesionsClinical course irregular and unpredictableSeverity of pruritus and inflammationSkin hyperirritabilityExacerbations by stress and irritant factors

mune abnormalities demonstrated in vitroand in vivo (Table III) are correlated withmostly decreased proliferative responses ofPBMCs to mitogens and antigens94. As a con-sequence, T cells express in AD patients lowlevels of ILs95 and less IL1 than healthy sub-jects96, whereas high concentrations of IL2Rare frequently observed when the eczema ismost florid, and are correlated with the ex-tension and the severity of the clinicalpattern97.

Perhaps more importantly the absolutenumber of T cells appears to be within thenormal range but it is decreased that of T-cellsubsets, especially the Th1-subpopulation:52% of T cells were Th2, 44% Th0, and only4% Th198. Studies on skin-derived Der p-spe-cific T cells in AD subjects reveal that 42,2%of T clones express the Th2 phenotype andonly 11,5% that of Th199, or 70% the Th2 and15% the Th0 subpopulations100. TheCD4/CD8 ratio in T-cell clones may be in-creased till to 200% compared to controls101,however other workers were unable to repro-duce these findings91,102. The Th1 dysregula-tion appears to reside in the CD29+ memorysubset, in this case not correlated to theseverity, or the extension of eczema, butprincipally to the decreased CD8 subpopula-tion, which in the skin infiltrate is definitelyless than that of CD4 cells94. Studies withAMLR (autologous mixed lymphocyte reac-tion), which is thought to represent an induc-er circuit for the activation of CD8+ effectorcells83 have found a marked deficiency or

decreased responsiveness in all studied pa-tients with AD, but also in individuals withno known evidence of skin disease103. Sincethe defect was associated with a reducednumber of circulating T cell bearing the sur-face marker CD29, the impaired generationof CD8+ is considered secondary to this de-fect. The quantitative deficit of CD8 has beenalso found in T allergen-specific clones ofatopic donors: 92% were CD4 and only 8%CD8 (11,5:1). In a subsequent study employ-ing flow cytometry and hemocytometry, theratio was 4:1, with the percentages of CD4cells significantly higher in chamber fluidsthan in peripheral blood, while the reversewas true for the CD8 lymphocytes104.

From a functional point of view, the regula-tion of in vitro IgE synthesis by CD8 cells,and the generation of Con-A-activated Tlymphocytes in atopic subjects appears to beabnormal91. However the significantly re-duced proliferation index in PBMC from ADpatients compared with normal PBMC maybe consistent with previous studies105. Such adeficit could occur in atopic individuals be-cause of the altered PGE2 regulation of CD8subsets105, even if the CD8 impairment mightalso be due to LTB4106. The flow cytometryshows a decrease in cytotoxic CD8 T cells ex-pressing S6F1bright107, a characteristic that,along with the similar impairment of NK-cellactivity, and according to the AD active andquiescent clinical stages as seen from TableIV108, may partially account for the increasedsusceptibility to viral infections, particularly

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Active phase Quiescent phase Normals

Mean ± SD Mean ± SD Mean ± SD

Chemotaxis 58,18 ± 18,75 57,13 ± 14,93 89,03 ± 5,19Cytotoxic activity 20,42 ± 4,41 26,61 ± 4,71 44,74 ± 5,18

Severity of AD (mean ± SD)

Mild Moderate Severe Normal

Cytotoxic activity 25,04 ± 1,87 20,39 ± 3,29 16,24 ± 2,77 44,74 ± 5,18

Table IV. Cytokine production by T-lymphocyte clones in AD.

p (patients versus controls) < 0.0001; SD = standard deviation.Adapted from 108.

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with Herpes simplex (HSV)109. The selectivealterations of NK-cell activity may be the re-sult of the severity of AD more than the dys-regulation of IgE antibodies, or of T-cell sub-populations94. In this regard, NK-cell activitycan be reduced in vitro by adding PGE2 andrestored by IFN-β and -γ addition110.

Suggestive findings support the concept ofa hereditary nature of the abnormalities ofcell-mediated immunity (CMI), since inneonates with a family history of atopy havebeen observed lower numbers of T cells thanin babies with no genetic predisposition foratopy111, as well as lower CD8 counts in 1-2-month-old infants who developed AD thanbabies who did not112. No univocal resultshave confirmed that the T-cell imbalance inAD is of primary nature94. Recent data sug-gest that there are no definite data corrobo-rating such a defect: it is true that in healthyinfants with AD aged 0-1 years the mean lev-el of CD8 cells was 5,5%, but this concentra-tion subsequently increased up to 7,5%113, inolder children aged 0-6 years there were noquantitative deficits of CD3, CD4, CD8 andCD19114. However CD8 levels are 21%, lessthan a half of CD4 levels (41%), ratio = 1,9,and B cells only 22,5%, evident especially inthe first year of life in healthy infants115.Consequently the Th2 lymphocytes, facingthe CD8 deficiency, trigger a vigorous prolife-rative response, leading to hyper IgE and theskin lesions. On the other side, from a generalpoint of view it is difficult to demonstrate thatAD develops earlier when at birth or duringthe first months of life there is a CD8 T cellnumber and function deficiency with parallelincrease of the CD4/CD8 ratio. Based on thisbackground, much remains to be clarified inrelation to the development of AD.

More crucial are the qualitative deficits;several data suggest an immune imbalance inlymphocyte activation, such as the decreasedfunction of cytotoxic T subsets (which againmay account for the increased frequency ofviral infections), in addition to the increasednumbers of non T non B cells and therestoration in vitro of both the number andfunction of lymphocytes116. However, ADcannot be simply defined as a clinical manif-estation of decreased CMI. More im-portantly, immunohistologic studies of thecellular infiltrate and studies directed at cir-culating parameters of CMI indicate a vigor-

ous T-cell activity in AD lesional skin83. Theincreased T-cell reactivity is correlated to thepredominant Th2 phenotype, which downreg-ulates the function and activation of the Th1cells: Th2 lymphocytes secrete a wide spec-trum of ILs, especially skin-derived IL4 thataffects the switch of immature B lymphocytesto antibody-secreting cells, and activates IgEreceptors on LC and monocytes infiltratinglesional skin, automatically antagonizing theexpression of Th1 and IL2R. It is of note thata reduced production of IFN-γ (on chromos-ome 12q22-24) has been found in cord bloodmononuclear cells cultures of neonates withpositive family history, therefore at high riskof developing atopic disease compared withneonates without family history of atopy117-121.

It is not known as yet exactly how the differ-ent types of T cell contribute to AD pathogen-esis95, nor which are their relationships withIgE antibodies. However both Th2 and IgEpredominance are coordinated. IgE synthesis ispromoted by IL4 and inhibited by IFN-γ68,122. Inaddition, there is a significant relationship be-tween the increase of IgE and IL4 levels: conse-quently several factors are likely to play a role:

• increase of Th2 subsets secreting IL4 andIL10 induced by IL1;

• establishment of a Th2-like pattern of ILproduction, due to specific clones ofallergen-specific CD4+ T lymphocyteswith an excess of Th2123, which drive anuninterrupted production of both IgEand ILs124;

• increased synthesis of IL4 and IL10 andthe ensuing inhibition of IL12, are the crit-ical factors underlying the aberrant ILproduction profile that promotes the sup-pression of IFN-γ production125,126;

• skin-infiltrating Th2 cells after allergenexposure secrete IL3-IL6 and GM-CSFwhich favor the migration, differentia-tion, and survival of IgE and eosinophils;

• over-expression of IL4 by allergen-stimu-lated mast cells, and of IL4 and PGE2 bymonocyte-macrophages infiltrating thechronic AD lesion, either of which in-hibits IFN-γ, thus further amplifying theTh2 response122,127,128;

• increase of PDE activity by stimulated Tcells, which has been suggested to directdifferentiation into Th2 type cells, with ahigh IL4 production90.

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Interestingly, the demonstration at the skinlevel of the concomitant release by PBMC ofatopic donors of reduced quantities of IFN-γand of substantial amounts of IL4

129, was de-tected only 2 h after the antigenic challengein mite allergen-induced dermatitis in atopicsubjects, even before the gene expression130,and in highly atopic children aged 5.4 years(mean)131. Thus in all likelihood the relevantexpansion of allergen-specific Th2 cells,through the upregulation of IL4 levels, have anongoing impact on the chronic stimulation ofIgE synthesis, on the induction of Fcε recep-tors on B cells and on molecules crucial forantigen presentation, such as monocytes andLC, as well as on the proliferation of mastcells and perhaps also of eosinophils throughIL5. The dominant role of T cells has beenconfirmed in vivo in children with AD by thespontaneous expression of IL4 mRNA ascompared to controls, although in neonatesand children under 10 years of age IL4 secre-tion was found to be significantly reduced132.There is evidence of high frequency of IL4-producing CD4+ allergen-specific T lympho-cytes in AD lesional skin and not at all IFN-γ,contrary to the findings in healthyindividuals100. Several workers have found inAD significantly lower IFN-γ concentra-tions133-136, and much higher of IL4 comparedto controls (p < 0.0001)136. It has been subse-quently shown that despite the reduced secre-tion of IFN-γ, atopic children have an

increased percentage of IFN-γ-producingcells in unstimulated PBMC cultures com-pared with controls, thus evidencing a post-transcriptional defect137. Consequently, theinability to secrete IFN-γ due to a possible im-paired IL12 or IL18 production138 together withthe abnormal T lymphocyte function maycontribute not only to the enhanced synthesisof IgE, but also to the high IgE levels in 80%of the children. The significant abnormalitieswhich sanction the exit of Th1 lymphocytesand Th1-like ILs may be of paramount imp-ortance to the pathogenesis either of atopy,or AD. A similar immune dysfunction is dir-ectly involved in children with WAS or AD85.

The pathogenetic role of IgE antibodies(atopic status)

We will now consider the influence of totaland specific IgE levels on the clinical mani-festations of AD. There are no doubts thatthe major immunologic contribution to pa-thogenesis is the IgE-mediated sensitization.Table V11,82,84-85,139-146 summarizes some im-portant features which speak in favor of therole of IgE antibodies, which recently hasbeen further strengthened in view of the fol-lowing points:

• precisation of the function of CD154which is known to play an important rolein the induction of the synthesis of IgE alsoin peripheral tissues, such as the skin10,28;

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1) Family history posi-tive for AD in 42-90% of children2) Statistically significant high IgE levels in about 80% of children3) About 85% of patients have positive immediate SPT and/or IgEs to a variety of food and inhalant allergens4) Serum IgE levels are highest in children with coexisting respiratory allergy5) Substantial evidence supports the notion that IgE levels are low during remissions, and higher during flaring

of AD6) 50-80% of children has coexisting allergic IgE-mediated manifestations such as AR and/or asthma, and food

allergy (FA)7) Positive/negative effects of bone marrow transplantation8) Several studies correlate eczematous flares with immediate and/or late-phase skin reactions after SPT and/or

patch tests with inhalant and allergens, for example after application of mite extract to the abraded skin ofsubjects with PTC positive for Der p 1

9) Association between clinical manifestations and food allergens in 30-50% of children; in 33% of subjects un-dergoing DBPCFC

10) Tthe removal from potential allergens in infants' home environment (sea resorts) leads to clearing of eczema-tous skin lesions

11) Flaring of skin lesions after exposure to environmental allergens and resolution after allergen elimination12) Reduced prevalence of AD in at risk babies if food allergens are eliminat-ed during the first year of life

Table V. Evidences in favor of the role of IgE in AD.

Adapted from 11, 82, 84, 85, 139-145.

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• identification of LC in vivo47;• presence of IgE anti-Staphylococcus au-

reus147,148 and anti-Candida149 in patientswith skin colonized by such agents.

In AD there are no definite data indicatinga preferential expansion of IgE-mediatedmechanisms, because the routine histologicalappearance of eczematous lesions rathershows a close resemblance to a classical typeIV cell-mediated hypersensitivity reaction,certainly not dominated by IgE15, although anot conventional one35. However, additionalevidence of the role of IgE-mediated mecha-nisms is indirectly confirmed by the recentdemonstration that:

• mechanisms involving IgE molecules inIgE-mediated skin reactions may also fol-low in the LPR (late-phase reaction), stillinvolving allergen activation of cutaneousmast cells bearing FceRI on their sur-faces150,

• the release of IL1 at sites of human cuta-neous allergic reaction during the DTHalso may be involved in the IgE-depen-dent inflammation of eczematous skinsince it is associated with the activationof LC96,

• children with AD developing reactions toa positive DBPCFC were found to have arise in plasma histamine levels but not af-ter placebo challenge151 in addition toskin reactions145,

• skin biopsy specimens of uninvolved sitesobtained before DBPCFC have not re-vealed the eosinophils which insteadwere found to infiltrate the skin lesions 4and 14 hr later151,

• food allergen-induced mast cell activationhas been shown to trigger either an imme-diate reaction or a LPR in the skin151,

• higher rates of spontaneous histamine re-lease from basophils in patients with ADand food hypersensitivity compared withcontrol subjects152,

• eosinophils link IgE molecules in skin le-sion through both FcεRI and CD23153,

• studies till yet referred to have evidencedthe presence also of FcεRII on the sur-face of several cells, such as eosinophils,macrophages and platelets154, thus readyto respond to IgE, and very plausibly in-volved in IgE-mediated skin reactions150.

These, and other cells, as well IgE mole-cules constitute the inflammatory infiltrate.During the early phase of mast cell activa-tion, patients developing a pruritic, erythe-matous, macular or morbilliform rash follow-ing relevant allergen exposure to a DBPCFCwere found to have an increase in plasma his-tamine139. Four to eight hrs following initialmast cell activation, onset of an IgE-depen-dent LPR occurs: biopsies obtained at the 8-hr limit reveal 48% lymphocytes, 27%eosinophils, 9% neutrophils, and 5% mono-cytes13. These two phases are thus character-ized by IgE-mediated hypersensitivity reac-tions. However the IgE system is not the onlyimmune pathogenic mechanism in AD, evenconsidering its place in LPR and FA: thereare several pieces of observation against therole of IgE antibodies in the pathogenesis ofAD. The role of anti-IgE is further enlight-ened by the points summarized in Table VI,often complementary to those analyzed inTable V155,156:

The role of Th2 cellsThere are several mechanisms regulating

selective migration of Th2-like lymphocytesinto lesional AD skin. T cells (4 × 1012 in theskin of a normal adult), typical componentsof SIS1, are the only cells within the involvedskin which proliferate on recognition of pro-

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• A marked elevation of serum IgE is found in sev-eral diseases, not neces-sarily atopic

• About 15-20% of normal children have high con-centrations of serum IgE without any clinicalmanifestation of atopy

• About 15-20% of children have AD without ap-parent signs of hyper IgE production

• The synthesis of IgE could be secondary to a func-tional imbalance of the immune mechanisms con-trolling it

• IgE antibodies are not a prerequisite for the de-velopment of skin lesions, since AD can manifestitself even in not atopic children

• The typical skin lesion, the pomphus, is not a spe-cific marker of IgE-mediated allergic reaction ofAD

• AD is present in patients with agammaglobuline-mia, normal IgE levels, and PTC negative for al-lergens, as well as in WAS

Table VI. Evidences against a role of IgE in AD.

Adapted from 155, 156.

cessed allergenic peptides presented by theAPC, become activated upon presentation ofallergens, consist predominantly of cells withimmune memory, are enabled to proliferateand recirculate, to be rapidly recruited to mi-grate to the target tissue, the skin, during hu-man cutaneous allergic LPR1,116,157. This tis-sue-selective homing is regulated in large partat the level of skin disease-related T cells bythe significant expression of CLA, that weknow as a skin homing receptor for T cells10.Influx of T lymphocytes into cutaneous sitesof inflammation may be stimulated by incr-eased expression of adhesion molecules onvascular endothelial cells, such as CD62E in-duced by IL1 and TNF-α10. The importance ofthe release of these IL in the local accumula-tion of inflammatory cells is highlighted bythe inhibition by neutralizing antisera to bothIL1 and TNF-α158. The ensuing transmigrationof memory CLA-T cells is possibly modu-lated by interactions among CD11a/CD54,and CD49d/CD29/CD106159. The activation issubstantiated by high levels of both CD62Eand CD49d/CD29 expressed by > 90% ofskin T lymphocytes104. This is, through the re-lease of several IL, the connecting point be-tween the synthesis of IgE, eosinophils, mastcells, monocytes and basophils158. Th2 cells, inaddition to controlling the synthesis of IgEand the infiltration of the eosinophils, mayplay therefore a direct role in the inflamma-tion, and on the production in the bone mar-row and maturation of mast cells and particu-larly of eosinophils, also playing a prominentrole in prolonging their local survival throughIL3-5 and GM-CSF66. Th2 lymphocytes inter-acting with eosinophils are known to haveupregulating effects on their growth, mobility,tissue localization and activation160 because oftheir high eosinophilotropic IL5 secretion161.The point reference for skin T cells is IL4,their growth factor, the cellular infiltrate inallergen-induced skin LPR expresses in-creased mRNA for IL3, IL4, IL5 and GM-CSF, yet no mRNA for IFN-γ162. However thesecretion of IL significantly increases byadding IL2 to the culture medium, demon-strating that T cells infiltrate skin sites after12 hr40 or after 12-24 hr162. Clearly IL2 andIFN-γ are active in healthy individuals, but inpatients with AD the levels are not signifi-cant163. The levels of IL2 are reduced also duethe poor production from PBMC164, unlike

IL4 and IL5165. Immunohistochemical analysis

of the inflammatory infiltrate in skin lesionsrevealed that the PBMC infiltrate in the epi-dermis consisted predominantly of T cells,with subsequent invasion of dermis followingRANTES stimulation54; however 5 hr afterantigen challenge also the levels ofchemokines IL8 and MCP-1 are significantlyhigher than the controls166. T cells bear theCD3+ /CD4+45RO+ surface antigens withclass II HLA markers11. In a pediatric cohortthe CD45RO were 87,9 ± 7,6% of CD4 ver-sus 6 ± 3,7 of CD45RA14, employing moresophisticated analysis the ratio was 9:1 and onperipheral blood about 2:1140, with an inverseratio in young infants167, at the age of onset ofAD168. The activated lymphocytes expressIL2R169, an observation confirmed by the sub-stantial expression of HLA-DR+ from en-dothelial cells and the CD4 antigen of LC164.In the absence of a definite association be-tween the extension of clinical lesions and thenumber of cutaneous T cells, this is signifi-cant between the number of CD4+ and thatof eosinophils after 24 hr, still noticeable 48hr after onset of the reaction169. During theaccumulation of T lymphocytes at the site ofallergen-induced LPR resident cells in theskin, such as keratinocytes, rather than infilt-rating leukocytes appear to be the source ofTh2-like IL: IL3-5, IL1, and IL8 chemotacticfor lymphocytes, GM-CSF and IL7 as growthfactors for some IL23.

It has become increasingly appreciated thatadditional cutaneous events are involved inthe activation of T cells, such as IL6 elicitedduring the allergen-induced immediate reac-tion and the LPR, closely correlated with theinfiltration of eosinophils. Since the inductionof IL6 does not result in the appreciable mi-gration of these inflammatory cells in injuredskin tissue, this may be mediated by the pre-dominant expression of another chemotacticfactor, for example PAF13. Studies in situ ofskin biopsies, in allergen-induced cutaneousLPRs in atopic subjects, have revealed theexpression only of Th2-like IL162, a not sur-prising occurrence, being the allergen-specificCD4 in lesional atopic skin by a large majori-ty Th264,98,100,135. Indeed PBMC of AD patientshave low levels of IFN-γ and high of IL4

64,while adding to the sopranatants of patientswith AD and controls an anti-IL4, theconcentrations of IFN-γ increase significantly

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only in the controls, whereas the concentra-tions of IgE in the patients are significantlyhigher than the levels of controls64. The in-ability to produce IFN-γ may further confirmthe raised IgE synthesis and sustained T-cellactivation observed in AD patients.

Surprisingly, the contemporary demonstra-tion of in situ expression of Th1-like (IFN-γand IL2) and Th2-like (IL4) in skin biopsysamples shows that skin lesions are notcaused by the exclusive expression of eitherTh1- or Th2-like ILs170. Recent studies sug-gest a two-phase model for the pathogenesisof AD, with a switch from an initial Th2 to aTh1 response in situ, that is a cutaneous LPRmediated by memory Th2-like cells secretingIL4 and IL5, histologically indistinguishablefrom the Th1- and IFN-γ-modulated LPR171.How can we differentiate the two phases?These apparently contrasting findings may in-dicate the different kinetics of IL4 and IFN-γexpression by T cells after allergen-specificstimulation172. Recent paradigms of the etiol-ogy of AD have suggested that in an earlyphase Th2-like ILs play a crucial role for ini-tiating eczematous lesions170, while with thesubsequent influx of Th1 cells, IFN-γ may becritical for the induction of keratinocyteCD54 expression170, also showing detrimentaleffects with the subsequent accumulation ofinflammatory cells in injured skin171. The ap-parent contradiction of LPR mediated byboth the Th1 and Th2 cells can be explainedby a study showing that also Th2 lymphocytesmay be crucial for the induction of atopiceczema173, by attracting inflammatory cellsand inducing IgE production171.

Children with food-induced AD providean unique opportunity for performing studieson the allergen-induced lymphocyteproliferation which have demonstrated thatin addition to IgE-mediated mechanisms Th1cells can release levels of IL2 and IFN-γ high-er than the controls174. Further evidence isshown in children with CM-induced AD,whose PBMC displayed significantly higherlevels of CLA than reactive T cells fromnonatopic control subjects or atopic childrenwithout AD175. Since the control subjectsfailed to express CLA one can postulate thatthe high CLA expression of casein-reactivecells may facilitate the localization in skin ofsuch T cells, thus playing a key role in deter-mining cutaneous lesions175. In addition fresh-

ly isolated circulating CLA+ T cells in pa-tients with AD, but not in normal controlsubjects, selectively highlighted both evi-dence of activation (HLA-DR expression),and spontaneous production of IL4 but notIFN-γ176, thereby showing to be Th2 cells.Accordingly we can outline a second phase ofinflammation when Th1 cells predominate inskin lesions171, along with Th1-like ILs suchas IL2 (and sIL2R) and IFN-γ but alsoIL4

162,170,177. Taken together, these observa-tions strengthen the two-phase model ofLPR, with an early phase dominated by Th2cells followed by a switch in Th1 cells. Thisswitch of profile is probably imposed by thegradual production of local IL12 that se-lectively promotes the production of IFN-γby T cells178. Thus far it is unclear which Th-like IL(s) contribute to perpetuate the localinflammation, otherwise the switch representsan attempt by the body to restore homoeostasisin the skin, which however is unsuccessful insubjects with AD171. The existence of two Tphenotypes may be explained considering theTh2 effector of the missed attempt of inh-ibiting Th1, to limit the tissue damage follow-ing the activation of these T lymphocytes. Wehave till yet stressed the severe deficiency ofIFN-γ in at risk neonates and infants: para-doxical results show on the one hand down-regulating effects on the IFN-γ responsecaused by the inhibition of IL12 due to excessproduction of IL4 and IL10

179, on the othersubstantial amounts of cells producing IFN-γin children with severe AD compared withnormal controls131. Finally the data regardingT cells are not convincing, being in themajority of cases the Th2 in the first place,implicated in the atopic responses, while T-cell clones specific for Candida albicans andtetanus toxoid of atopic donors mainly pro-duce Th1-like ILs83, confirming that thedifferentiation of Th0 into Th1 or Th2 alongwith the distorted IL profile is determined bythe characteristics of the allergens in additionto genetic factors66. In this regard, recentstudies support the likelihood that agenetically determined aberrant expressionof type-2 ILs may play a role in certain pa-tients. Indeed the studies indicate an associa-tion between high levels of total IgE and in-creased expression of genes located in the re-gion of chromosome 5q in position 31-33180-

182. It is not without significance that the clus-

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ter of genes of type-2 ILs IL3, IL4, IL5 IL9,IL13 is located in the same locus, along withGM-CSF, IL6, CSF and CD14183.

The role of inhalant allergensSince 1918184 there is mounting evidence

that percutaneous absorption of allergens cancontribute to AD pathogenesis. Studies havedemonstrated that contact with or inhalationof aeroallergens can trigger the typical skinlesion of AD in some patients, who also ex-perience eczematous flaring following expo-sure to ragweed pollen185. In addition,Cohen186 did a very interesting observation,which definitively showed that pollens canreach cutaneous mast cells. His study clearlydocumented the rapid absorption of pollenthrough the respiratory mucosa and trans-ported to distal skin mast cells186. Ragweedpollen was blown into the nostrils of 50 nor-mal control subjects passively sensitized in-tracutaneously with serum from a ragweedallergic patient and serum from non-atopiccontrols. Within a mean of 20 minutes all testsubjects developed a wheal-and-flare re-sponse at the sensitized site but not at thecontrol site. Hopkins et al187 were able to in-duce in a patient asthma and flares of ADfollowing inhalation of an Alternaria spray.Tuft et al attempted to establish the pathog-enic role of inhaled pollens in AD. Theyhypothesized that inhalation of pollen led tosweating, which was linked to the develop-ment of pruritus and subsequent AD lesions.Eczematoid changes developed which persis-ted for several days188,189. Tuft et al performedinhalation studies also with Alternaria: sweat-ing and pruritus developed within minutes,and changes over 12-24 h developed in skinsites, which lasted for 4-5 days190. Rajka con-firmed these data in 2/5 patients with “pure”AD, who developed skin lesions followingthe inhalation of a mould extract191. The in-halation studies of ragweed and Alternariaprovided the first evidence for a pathogenicrole of aeroallergens in patients with AD.

Several studies of the early ’50 have alsoshown that house dust exposure may influ-ence the clinical outcome of AD. However, itis of note that more than 50 years ago, Rostdemonstrated that the skin lesions remark-ably improved when patients with AD werekept in a dust-free environment192. Thereforeinhalation of Der p allergen, as ragweed

could play a role in the pathogenesis ofAD185. Mitchell et al first suggested that theskin lesions of AD could be provoked evenby contact with Der p193. Repeated patch tests(PT) with aqueous Der p 1 extract on lightlyabraded skin were performed in 10 adult pa-tients with AD. Only patients with positiveSPT to Der p had positive PT. PT was alsopositive in 4/6 atopic adults not sufferingfrom AD. At 72 hrs epidermal changes, incl-uding focal spongiosis and microvesiculationwere evident along with a significant increasein the number of basophils and eosinophils.Biopsy specimen of the positive lesions alsoshowed mononuclear cell and neutrophilinfiltration193. Eczematous lesions on not ma-nipulated skin appeared in 3/17 patients withAD following PT employing Der plyophilized commercial preparation. Biopsiesof the positive test sites revealed an eczema-tous reaction with epidermal spongiosis andmicrovesiculation. Immunostaining of cryo-stat sections showed dermal cell infiltratesconsisting of mainly T lymphocytes. Therewas a smaller proportion (0-30%) of LC cellsand the number of mast cells and basophilswas usually 5-10%194. Typical AD lesion oc-curred on non manipulated skin in 4/13 adultswith AD by applying twice a day for 2-5 daysan ointment containing Der f195. Gondo et alalso demonstrated the penetration of Der f(which was linked with ferritin) into the stra-tum corneum, the epidermis and the dermis.However, the lesions were present only intypical areas and only with previous skinscratch. The authors hypothesized that AD,rather than being primary eruption, is likelyto be the result of various repeated stimuli,combining reactions including type I and typeIV immunoreaction with a primary irritantresponse to a combination of physical, chemi-cal, and mechanical factors, including scratch-ing due to persistent itching. In fact followingthe percutaneous challenge with mite aller-gen, a type I reaction occurred in the pa-tients. A delayed type IV reaction occurredon repeated challenge195.

Adinoff et al and Clark et al196-198 eliciteddelayed cutaneous response in 18 patientswith AD applying various aeroallergen ex-tracts (20 w/v in 50% glycerin) on clinicallyuninvolved and not manipulated skin. Onlypatients with positive SPT response to Der phad positive PT response to Der p. Atopic

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patients not suffering from AD failed to showpositive PT responses. Norris et al199 appliedfor 5 days 1 ml of a PT solution containingDer p on the unmanipulated antecubital orpopliteal skin of atopic adults with or withoutAD. Worsening of the skin lesions occurredin 1/3 patients with AD and positive PT re-sponse to Der p. All patients with AD andnegative SPTs to Der p had negative PT resp-onse. Bruijnzeel-Koomen et al40 showed 70%positive PT response, applying house dustmite (and pollen allergens) on the back ofAD adult patients, previously removing thesuperficial stratum corneum by 15 con-secutive applications of adhesive tape. Nopositive responses were found in atopic pa-tients without AD or in controls. Positive PTreactions were not found in normal controlsor atopic patients without AD. These PTscaused eczematous lesions. Analysis of thecellular infiltrate demonstrated an influx ofeosinophils into the dermis, starting from 2-6hours after patch-testing. Immunostainingwith antibodies against granular constituentsof the eosinophils revealed that infiltratingeosinophils were in an activated state andhad lost part of their granular contents. At 24hours eosinophils also appeared in the epi-dermis. Histologically, a predominance of Tcells of the helper/inducer phenotype havebeen observed. Recent data have confirmedthe prevailing role of Der p in PT lesions, andthe close association of the allergens withTh2 lymphocytes100. It has been speculatedthat immediately after PT-testing some aller-gens penetrate the epidermis, bind the IgEmolecules on mast cells in the dermis andinduce an immediate type reaction. Mast cellsrelease eosinophil chemotactic factors andsome of the infiltrating eosinophils becomeactivated50. Activated eosinophils which havelost their granular contents are seen in PT le-sions: electron microscopy showed that someepidermal eosinophils were in close contactwith LCs, thus suggesting a cell-cell interac-tion40.

Recent studies show that in the skin lesionsthe predominant atopic patients’ Der p-spec-ific T-cell clones are Th2 cells expressing IL4

and IL5 and not IFN-γ. On the contrary nonatopic Der p-specific T-cell clones all pro-duced IFN-γ and only in some cases a mini-mal amount of IL4

123,161. Thus the dysregula-tion of IgE synthesis in AD reaches its apex,

in the absence of IFN-γ. IFN-γ is absent in thethe cord blood of atopic neonates, however itis speculated that even the poor productionof IFN-γ is predictive of AD development200.

The role of food allergens It has been suggested that chronic inges-

tion of the offending food(s) leads to cuta-neous irritability, basophil releasability andactivation201. Release of mediators as aconsequence of an IgE reaction, and highlevels of serum histamine have been shownin children with AD after a positiveDBPCFC response151; but histamine releaseonly (at the gastrointestinal and/or skin lev-el) cannot completely explain the histologyof the skin lesions, which is more indicativeof a type IV cell-mediated response151. Animportant role is played by the late phase ofIgE-mediated hypersensitivity, and evidenceis accumulating that eosinophils actively par-ticipate in allergic LPR in different tissues,including the skin27. When the ingested foodantigens come into contact with the skinmast cells, histamine and other chemo-attractants are released into skin tissue. It isstriking the negative effect on basophils andSBHR levels set forth by food allergen iden-tification and elimination. The repeated in-gestion of food allergens was discovered tobe associated with a spontaneous productionof histamine-releasing-factor (HRF) pro-duced by PBMC in vitro and in vivo. Bybinding to surface-bound IgE molecules andbasophils, HRF(s) may perpetuate histaminerelease and induce allergic reactions whichare too delayed or too prolonged to be con-sidered classic IgE-mediated reactions. Thefinding that IgE molecules from atopic pa-tients bind HRF but that IgE antibodiesfrom non-atopic subjects do not suggests thatthese molecules have a great deal of clinicalsignificance. These HRF are able to promotea continuous histamine release from mastcells and basophils, and increased skinhyperirritability due to a variety of minornonspecific stimuli including additives, deter-gents, heat, and cold152. It has been shownthat spontaneous basophil histamine release(SBHR) is high in children with food indu-ced AD while they are not on an restricteddiet but it is close to normal when these chil-dren are on an elimination diet152. SBHRcorrelates to the HRF production from

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PBMC and HRF may activate or decreasethe activation threshold of both basophilsand mast cells and could explain the highSBHR described in patients with AD152.

The contributing role of food allergens inthe pathogenesis of AD has been establishedby DBPCFCs145,201-203 and confirmed by signif-icant improvement after appropriate elimina-tion diet204-207. We have evaluated the efficacyof a CM- and/or egg-free diet in 59 childrenaged 2-14 yr suffering from severe AD206. Theelimination of CM and/or egg for 4 weeks re-sulted in the healing, or marked im-provement of skin lesions in 96% of chil-dren206. Sampson who has devoted most ofhis work to original studies in the field of ADand FA has evaluated children aged 3 mo-25yr: in the patients studied, 412 DBPCFC(64%) were negative and 235 (36%) werepositive, and 130 (55%) reacted to at leastone food. Overall, 174/235 reactions (75%)involved the skin201. In addition, it was shownthat eggs, peanuts, CM, wheat, fish, and soy-beans accounted for nearly 90% of the posi-tive reactions in AD patients. Most of thesechildren (78%) reacted to one or two offoods, 15% to three foods and only 3 childrento four or more different food145. Thus food-induced AD appears to be rather specific interms of the number and identity of theimplicated foods.

In a subsequent study of ours207, 146 chil-dren with AD aged 6 mo-10 yr underwent 154challenge tests, 61 of which (42%) were posi-tive. In detail 42/101 challenges with CM(42%) and 19/45 with egg (42%) were posi-tive. The symptoms elicited were either im-mediate or delayed (Table VII)207. Employingtwo foods (CM and egg) for challenges, we

have obtained positive reactions in 75% ofchildren207, a figure very similar to that ofSampson145. Foods frequently reported to in-duce hypersensitivity such as citrus fruit,chocolate, strawberries145, did not elicit posi-tive responses in our patients207. The highnumber of positive SPT and RAST to foodsfound in children with AD supports the fre-quent observation that children with AD areoften allergic to a large variety of foods. Evenif children consume a wide variety of differentfoods, the most common foods of the Italiandiet such as CM, egg and wheat accounted formore than 93% of the positive responses. Thisdata should be evaluated in order to eliminatethe nutritional problems of too restrictive di-ets. As regards the allergenicity of soy, wehave reviewed 6 studies employing challengetests to soy, which were positive in 4,2% of2496 children aged 0.4-18 years. In addition inSPT-RAST-oral food challenge/DBPCFC-based 17 epidemiological studies soy inci-dence attains 3%208. On the contrary, CM is soa potent allergen that a drop is enough to pro-voke anaphylaxis in allergic infants209.However, children developing tolerance caningest normal quantities of foods without clin-ical manifestations, despite the fact that SPTand RAST usually remain positive201.

The role of skin infections andbacterial superantigens

Microbial pathogens initiate diseasethrough a number of pathways. Certain bac-terial components may be directly responsi-ble for disease, since they can stimulate largenumbers of lymphocytes. The recently de-scribed family of microbial superantigenshave the ability to function as potentimmunoregulatory compounds. On the otherside patients with AD have an increased sus-ceptibility to a variety of microbial agents.Recently a greatest focus has been con-centrated on the significance of Staphy-lococcus aureus colonization and infection tothe severity of AD skin lesions210. More than50% of the AD patients secreted staphylo-coccal enterotoxins and others such as11: SEA= staphylococcal enterotoxin A, SEB =staphylococcal enterotoxin B, SEC =staphylococcal enterotoxin C, SED = staphy-lococcal enterotoxin D, SEE = staphylococcalenterotoxin E and TSST-1 = toxic shock syn-drome toxin-1.

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Table VII. Clinical reactions elicited in 61 children posi-tive to challenge tests.

Adapted from 207.

Symptoms N° of children (%)

AD worsening 30 (49%)Pruritus 28 (46%)Rash/erythema 26 (43%)Urticaria 14 (23%)Asthma 9 (15%)Lip edema 5 (8%)Diarrhea 4 (6%)Vomiting 2 (3%)

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The capacity of bacterial toxins to bindMHC class II molecules or stimulate T cellsbearing TcR Vß’s suggest several mechanismsby which SEs could exacerbate AD.

1) SEs secreted at the skin surface couldpenetrate inflamed skin and engageHLA-DR on macrophages or LC to stim-ulate the production of IL1 and TNF, ILwith potent proinflammatory properties.

2) SEs could stimulate T cells via their TcRVβ to divide and release ILs which mod-ulate tissue inflammation.

3) Nearly 50% of AD patients have circu-lating IgE antibodies directed to SE,such as TSST-1 or SEB. These toxinshave been identified on their skin11.

Eight patients survivors of toxic shock syn-drome had TSST-1 producing staphylococciand dermatitis, and four of them had in-creased IgE levels (median 290 kIU/l)suggesting AD. AD might therefore be a con-sequence of immune activation during expo-sure to SEs, in addition TSST-1 bound tokeratinocytes may disturb the IL repertoire,thus enhancing IL4 and IgE antibodies211.

Concluding Remarks

AD is a disease of offsprings of atopic par-ents, infants and little children, who can beeasily identified and subjected to preventa-tive measures, the first treatment forAD212,213. While FA appears to be transitory,the frequency of positive SPT between 1 and7 years of age increased for mite 14,3 and forpollens 31,5 times214, probably for insufficientprevention212. It is conceivable that the com-ing years will witness the development of newstrategies for the prevention and treatment ofAD, aimed at specific targets based on athorough understanding of its pathogenesis.

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