An overview of primary immunodeficiency diseases 2014

In the Name of God the Merciful the BneficientIn the Name of God the Merciful the Bneficient

Overview of Primary Overview of Primary Immunodeficiency Immunodeficiency

DisordersDisorders((PIDsPIDs))

Mostafa Moin MDMostafa Moin MDProfessor of Allergy & Clinical Immunology Professor of Allergy & Clinical Immunology

Immunology, Asthma & Research InstituteImmunology, Asthma & Research Institute

IAARIIAARI

Tehran Univesity of Medical SciencesTehran Univesity of Medical Sciences13921392-- 20142014

Key Roles of Immune SystemKey Roles of Immune System

Prevent and control Prevent and control infectioninfection Prevent and control Prevent and control autoimmune diseasesautoimmune diseases Prevent and control Prevent and control malignancymalignancy Prevent and control Prevent and control allergic diseasesallergic diseases Prevent and control Prevent and control graft-versus-host (GVH)graft-versus-host (GVH)

Host Immune Defense MechanismsHost Immune Defense Mechanisms

Non-specificNon-specific --InnateInnate BarriersBarriers

– SkinSkin– Secretions (mucous, Secretions (mucous,

tears, saliva)tears, saliva)– Mucociliary clearance, Mucociliary clearance,

peristalsisperistalsis PhagocytesPhagocytes

– NeutrophilsNeutrophils– MacrophagesMacrophages

ComplementComplement CytokinesCytokines

Specific -Specific - Acquired Acquired HumoralHumoral (antibodies) (antibodies)

CellularCellular (lymphocytes)(lymphocytes)

Innate and Acquired ImmunityInnate and Acquired Immunity

InnateInnate AcquiredAcquired

Ag specificityAg specificity nono yesyes

Magnitude (Magnitude (1100, , 2200)) samesame higher (higher (2200 > > 1100))

MemoryMemory nono yesyes

Key componentsKey components PMN, NKPMN, NK T, B lymphocytesT, B lymphocytesC’, C’, barriersbarriers APCsAPCs

Cytokines, Chemokines,Adhesion molecules

Types of Immuno-deficienciesTypes of Immuno-deficiencies

6

Defects in some components of the immune systemDefects in some components of the immune system

- - Gene defectGene defect

Increased frequency, severity and Increased frequency, severity and duration of duration of infectioninfection

Unexpected Unexpected complicationscomplications or unusual or unusual manifestations of infectionmanifestations of infection

Infection with Infection with organismsorganisms normally normally considered of considered of low pathogenicitylow pathogenicity

Noninfectious manifestationsNoninfectious manifestations in in gastrointestinal, endocrinologic, gastrointestinal, endocrinologic, hematologic organ systemshematologic organ systems

Clinical Features of Primary ImmunodeficiencyClinical Features of Primary Immunodeficiency

Recurrent respiratory infectionRecurrent respiratory infection Persistent sinus infectionPersistent sinus infection Paucity of lymphoid tissuePaucity of lymphoid tissue Failure-to-thrive in infantsFailure-to-thrive in infants Skin lesions (rash, pyoderma, eczema, Skin lesions (rash, pyoderma, eczema,

telangiectasia)telangiectasia) Oral and perineal candidiasisOral and perineal candidiasis Diarrhea and malabsorptionDiarrhea and malabsorption

Clinical Findings in Primary ImmunodeficiencyClinical Findings in Primary Immunodeficiency

Accurate diagnosis and Accurate diagnosis and classification of PID is necessaryclassification of PID is necessary

To decide on appropriate To decide on appropriate clinical managementclinical management

To enable ininformed To enable ininformed genetic counselinggenetic counseling

To permit the systematic collection of data on PID To permit the systematic collection of data on PID through through registriesregistries that will facilitate further study that will facilitate further study of these rare diseasesof these rare diseases

To highlight the advances in To highlight the advances in gene therapygene therapy

9

WHY?

PIDs PrevalencePIDs Prevalence

Texbooks report Texbooks report 1 in 100001 in 10000 1999 U.S. Immunodeficiency Foundation 1999 U.S. Immunodeficiency Foundation

Survey found Survey found 1 in 50001 in 5000 2007 telephone survey of 27000 2007 telephone survey of 27000

household members found household members found 1 in 12001 in 1200 Antibody deficienciesAntibody deficiencies account for account for

approximately approximately 65%65% of PID cases of PID cases

International Union of Immunological SocietiesInternational Union of Immunological Societies New York City, May 31-June 1, 2011New York City, May 31-June 1, 2011

Table 1 | Table 1 | Combined immunodeficienciesCombined immunodeficienciesTable 2 | Table 2 | Well-defined syndromes with immunodef.Well-defined syndromes with immunodef.Table 3 | Table 3 | Predominantly antibody deficienciesPredominantly antibody deficienciesTable 4 | Table 4 | Diseases of immune dysregulationDiseases of immune dysregulationTable 5 | Table 5 | Congenital defects of phagocyte number,Congenital defects of phagocyte number, function, or bothfunction, or bothTable 6 | Table 6 | Defects in innate immunityDefects in innate immunityTable 7 | Table 7 | Autoinflammatory disordersAutoinflammatory disordersTable 8 | Table 8 | Complement deficienciesComplement deficiencies

PID Classification:2011-IUISPID Classification:2011-IUIS

Immunopathologic Basis of PIDImmunopathologic Basis of PID

Four Major Host Defense DeficienciesFour Major Host Defense Deficiencies

2.2. T-cell or combined T-cell or combined immunodeficienciesimmunodeficiencies

3.3. Phagocyte disordersPhagocyte disorders

4.4. Complement disordersComplement disorders

1.1. B-cell (B-cell (humoral) immunodeficiencieshumoral) immunodeficiencies

IgG Antibody Levels Vary with AgeIgG Antibody Levels Vary with Age

Rules of thumb:Rules of thumb:-Quantitative IgG< 1000 is abnormalQuantitative IgG< 1000 is abnormal-Quantitative IgM< 100 is abnormalQuantitative IgM< 100 is abnormal-Quantitative IgA< 10 is abnormalQuantitative IgA< 10 is abnormal

Deficient Serum Antibody LevelDeficient Serum Antibody Level

Symptoms of antibody deficiencySymptoms of antibody deficiency

RecurrentRecurrent upper and lower respiratory upper and lower respiratory infectionsinfections

Severe bacterial infections with Severe bacterial infections with polysaccharide encapsulated bacteriapolysaccharide encapsulated bacteria

Paucity of lymph nodes Paucity of lymph nodes and tonsilsand tonsils Immune cytopeniasImmune cytopenias AutoimmunityAutoimmunity - arthritis, SLE - arthritis, SLE DiarrheaDiarrhea and malabsorption and malabsorption

MalignanciesMalignancies

BacteriaBacteria:: pneumococcus, H. flu, pneumococcus, H. flu, meningococcus, Staph aureus, meningococcus, Staph aureus, Pseudomonas, CampylobacterPseudomonas, Campylobacter

MycoplasmaMycoplasma, ureaplasma, ureaplasma VirusesViruses:: enterovirusesenteroviruses, rotavirus, rotavirus ProtozoaProtozoa:: giardia, cryptosporidium giardia, cryptosporidium Common organismsCommon organisms are still the most are still the most

common - but typically more severe and common - but typically more severe and difficult to treatdifficult to treat

Antibody Deficiency Infectious OrganismsAntibody Deficiency Infectious Organisms

Agammaglobinemias (XL,ARAgammaglobinemias (XL,AR)) Common Variable ImmunodeficiencyCommon Variable Immunodeficiency IgA deficiencyIgA deficiency IgG subclass deficiencyIgG subclass deficiency Specific antibody deficiencySpecific antibody deficiency Transient hypogammaglobinemia of Transient hypogammaglobinemia of

infancyinfancy

PrimaryPrimary Antibody DisordersAntibody Disorders

Antibody def.-Bruton's diseaseAntibody def.-Bruton's disease

X-linked agammaglobulinemia X-linked agammaglobulinemia (XLA)(XLA) Marked reductionMarked reduction in in all Ig classesall Ig classes, , B cell numbersB cell numbers

& & production of specific antibodiesproduction of specific antibodies Normal number and function of T cellsNormal number and function of T cells Defect in Bruton`s tyrosine kinase geneDefect in Bruton`s tyrosine kinase gene, B cell , B cell

development “frozen” at early precursor stagedevelopment “frozen” at early precursor stage Beginning Beginning after 6 months after 6 months of age,recurrentof age,recurrent

sino-pulmonary Infectionssino-pulmonary Infections

Antibody def.-Bruton's diseaseAntibody def.-Bruton's disease

DiarrheaDiarrhea due to giardia, due to giardia, Invasive infections Invasive infections

(sepsis, meningitis) due to encapsulated bacteria (sepsis, meningitis) due to encapsulated bacteria (pneumococcus, meningococcus)(pneumococcus, meningococcus)

Skin/soft tissue infectionsSkin/soft tissue infections Generally no increased severity of viral infections,Generally no increased severity of viral infections,

but at risk for chronic multisystem inf. due tobut at risk for chronic multisystem inf. due to

enteroviruses enteroviruses (including dermatomyositis- like (including dermatomyositis- like

synd. , hepatitis,meningoencephalitissynd. , hepatitis,meningoencephalitis))

Antibody: Common variable Antibody: Common variable

immunodeficiency immunodeficiency -- CVIDCVID

OnsetOnset usually in usually in 2nd to 4th decade 2nd to 4th decade of lifeof life Slow decline Slow decline in all classes of immunoglobulinin all classes of immunoglobulin Recurrent sinopulmonary Recurrent sinopulmonary infections (usually infections (usually

bacterial in origin)bacterial in origin) Gastrointestinal, endocrine, hematologic and Gastrointestinal, endocrine, hematologic and

autoimmune disorders autoimmune disorders can be associatedcan be associated May follow May follow Epstein-Barr infectionEpstein-Barr infection Increased incidence of Increased incidence of lymphoreticular malignancieslymphoreticular malignancies Genetic defect?Genetic defect?

Antibody: IgA deficiency Antibody: IgA deficiency

IgA< 5 IgA< 5 mg/dlmg/dl Most common Most common (1:400- 1:1000)(1:400- 1:1000) Often asymptomaticOften asymptomatic, may have recurrent , may have recurrent

sinopulmonary infectionssinopulmonary infections May co-exist with IgG subclass deficiencyMay co-exist with IgG subclass deficiency AllergyAllergy / / autoimmunityautoimmunity No treatmentNo treatment (only for infections) (only for infections) Genetic defect?Genetic defect?

Transient hypogammaglobulinemia of infancyTransient hypogammaglobulinemia of infancy- Maturational delayMaturational delay with low, persistent nadir in Ig production: with low, persistent nadir in Ig production:

normal event in preterm infantsnormal event in preterm infants- Usually Usually recurrent sinopulmonary infectionsrecurrent sinopulmonary infections- Usually normal B cell numberUsually normal B cell number and and response to immunizationresponse to immunization IgG subclass deficiencyIgG subclass deficiency- Commonly overdiagnosedCommonly overdiagnosed but may be significant if specific but may be significant if specific

antibody production also lowantibody production also low- IgG2, 4-infection with encapsulated bacteriaIgG2, 4-infection with encapsulated bacteria- IgG3-recurrent respiratory infectionsIgG3-recurrent respiratory infections- May occur in association with IgA deficiencyMay occur in association with IgA deficiency and evolve to and evolve to

common variable immunodeficiencycommon variable immunodeficiency

Antibody deficienciesAntibody deficiencies

Antibody: Hyper IgM SyndromeAntibody: Hyper IgM Syndrome

X-linkedX-linked, , defect in CD40 ligand defect in CD40 ligand expression (CD1540)expression (CD1540) 1: 500000, 90% by age 4 yrs old1: 500000, 90% by age 4 yrs old Recurrent sinopulmonary and invasive infections due to Recurrent sinopulmonary and invasive infections due to

encapsulated bacteriaencapsulated bacteria Recurrent neutropenia Recurrent neutropenia associated with oral ulcers and perirectal associated with oral ulcers and perirectal

abscessesabscesses Opportunistic infections caused by Opportunistic infections caused by Pneumocystic jiroveciPneumocystic jiroveci, CMV, , CMV,

adenovirus, adenovirus, CryptococcusCryptococcus, and mycobacteria, and mycobacteria Chronic diarrhea due to Chronic diarrhea due to GiardiaGiardia or to or to Cryptosporidium,Cryptosporidium,

SalmonellaSalmonella, or , or EntamoebaEntamoeba histolyticahistolytica Markedly reduced IgG & IgAMarkedly reduced IgG & IgA; ; high or normal IgMhigh or normal IgM Normal numbers of B and T cellsNormal numbers of B and T cells

Secondary hypogammaglobulinemiaSecondary hypogammaglobulinemia

MedicationsMedications, especially anticonvulsants, especially anticonvulsants Protein-losing Protein-losing enteropathyenteropathy NephroticNephrotic syndrome syndrome IymphoproliferativeIymphoproliferative disease disease Non-Hodgkin`s Non-Hodgkin`s IymphomaIymphoma Multiple myelomaMultiple myeloma

CD4+ cells: CD4+ cells: – DTHDTH– Helper function for Helper function for

• Cellular cytotoxicityCellular cytotoxicity• Ig synthesisIg synthesis

CD8+ cells: CD8+ cells: – T-cell cytotoxicityT-cell cytotoxicity– T suppressor cellT suppressor cell

T cells/combined immunodeficiencyT cells/combined immunodeficiency

T cells/combined immunodeficiencyT cells/combined immunodeficiency

T cells required T cells required for orchestrating adaptive immunityfor orchestrating adaptive immunity Loss of CD4Loss of CD4 (helper) T cells results in (helper) T cells results in combined cellular combined cellular

and humoral immunodeficiencyand humoral immunodeficiency, even if B cells are normal, even if B cells are normal Deficiency results in infections with:Deficiency results in infections with:- virusesviruses-particularly herpes group-particularly herpes group- Intracellular bacteriaIntracellular bacteria-e.g., Mycobacteria, Listeria-e.g., Mycobacteria, Listeria- ProtozoansProtozoans-pneumocystis, toxoplasma, cryptosporidium, -pneumocystis, toxoplasma, cryptosporidium,

giardiagiardia Antibody production to newly encountered microbes also Antibody production to newly encountered microbes also

compromisedcompromised

Functional Classification T cells/combined Id.Functional Classification T cells/combined Id.

Severe Combined ImmunodeficiencySevere Combined Immunodeficiency

Presentation usuallyPresentation usually< 6-12 mo age< 6-12 mo age Opportunistis infections Opportunistis infections and recurrent pyogenic and recurrent pyogenic

infections, chronic infections, chronic

diarrhea , FTT, eczemadiarrhea , FTT, eczema Male:Male: female 4:1 (most common female 4:1 (most common

form is X-linked)form is X-linked) Often fatalOften fatal befor 1 year of age if untreated befor 1 year of age if untreated Decreased number of T cells, variable numbers of B Decreased number of T cells, variable numbers of B

cells, poor proliferation to mitogenscells, poor proliferation to mitogens Low or absent IgG and IgALow or absent IgG and IgA

(SCID)(SCID)

Severe deficits in Severe deficits in cellularcellular and and humoralhumoral immunity immunity Classified byClassified by inheritance patterninheritance pattern and and pattern of pattern of

lymphocytes presentlymphocytes present X-linked:X-linked: IL-2RIL-2Rγγ chain chain-more than half of all cases-more than half of all cases Same Same γγ chain found in many interleukin chain found in many interleukin

receptorsreceptors Autosomal recessiveAutosomal recessive:: RAG, ADA/PNP, JAK3, IL-7Ra, ZAP-70RAG, ADA/PNP, JAK3, IL-7Ra, ZAP-70

Severe Combined ImmunodeficiencySevere Combined Immunodeficiency(SCID)(SCID)

X-linked T- , NK, B+ phenotype 60% of SCID, gene identified in 1992 Defective gene encodes the cytokine common gamma chain Mild lymphopenia (mean ALC 1500) 40% have a positive family history Adenosine Dearninase (ADA) deficiency-AR 15% of all SCID Early onset Profound lymphopenia Clinically heterogeneous ADA is a widely expressed enzyme, involved in purine metabolism Build up of toxic metabolic products toxic to T cell development


RAG1 and RAG2 Deficiency- ARRAG1 and RAG2 Deficiency- AR T- , B-, NK+T- , B-, NK+ 10% of SCID genes identified in 198910% of SCID genes identified in 1989 RAG1 and RAG2 form a heterodimer that is required to initiate VDJ RAG1 and RAG2 form a heterodimer that is required to initiate VDJ

recombinationrecombination Moderate lymphopenia (mean ALC 1000)Moderate lymphopenia (mean ALC 1000) Amino acid substitutions can cause Omenn Syndrome (SCID with Amino acid substitutions can cause Omenn Syndrome (SCID with

hyper-eosinophilia)hyper-eosinophilia)

JAK-3JAK-3 T-, NK-, B+ phenotypeT-, NK-, B+ phenotype 7% of SCID gene identified in 19947% of SCID gene identified in 1994 Defective gene encodes a lyrosine kinase activated by the Defective gene encodes a lyrosine kinase activated by the

cytokine common gamma vhaincytokine common gamma vhain Mild lymphopenia (mean ALC 1500)Mild lymphopenia (mean ALC 1500)


Other Forms of T cell/combinedOther Forms of T cell/combined Immunodeficiency Immunodeficiency

Purine nucleoside phosphorylase (PNP) deficiency –ARPurine nucleoside phosphorylase (PNP) deficiency –AR Rare form of cellular deficiency associated with defective Ab Rare form of cellular deficiency associated with defective Ab

production and autoimmunityproduction and autoimmunity May present later in childhoodMay present later in childhood 2/3 of patients develop progressive neurological manifestations2/3 of patients develop progressive neurological manifestations

Ataxia- Telangiectasia- ARAtaxia- Telangiectasia- AR Mutation in protein required for DNA repairMutation in protein required for DNA repair Ocular telangiectasias, cerebellar ataxiaOcular telangiectasias, cerebellar ataxia Recurrent sinopulmonary infections: variable IgA, IgG2, IgG4 and Recurrent sinopulmonary infections: variable IgA, IgG2, IgG4 and

Tcell deficitsTcell deficits Risk of Malignancy in patients and carriersRisk of Malignancy in patients and carriers


DiGeorge Syndrome Developmental field defect of 3Developmental field defect of 3rdrd and 4 and 4thth branchial branchial

arches due to chromosomal deletion (22q)arches due to chromosomal deletion (22q) Cardiac/great vessel > parathyroid > thymic defectCardiac/great vessel > parathyroid > thymic defect Severe hypocalcemiaSevere hypocalcemia Charactristic facies: mandibular hypoplasia, Charactristic facies: mandibular hypoplasia,

hypertelorismhypertelorism Great variability in the severity of T cell abnormality Great variability in the severity of T cell abnormality

(<1% have thymic aplasia with absence of T cells)(<1% have thymic aplasia with absence of T cells)


Wiskott-Aldrich SyndromeWiskott-Aldrich Syndrome X-linked partial combined immune deficiencyX-linked partial combined immune deficiency ThrombocytopeniaThrombocytopenia, , eczemaeczema and and recurrent infectionsrecurrent infections Sinopulmonary, herpes group viruses and Sinopulmonary, herpes group viruses and

occasionally Pneumocystisoccasionally Pneumocystis Few, small platelets; elevated IgE, reduced IgMFew, small platelets; elevated IgE, reduced IgM Defect in cytoskeletal organization by WaSp (wiskott Defect in cytoskeletal organization by WaSp (wiskott

Aldrich Syndrome protein)Aldrich Syndrome protein)

X-linked lymphoproliferative disorderX-linked lymphoproliferative disorder (XLP or Duncan Disease) (XLP or Duncan Disease)

1 in 10000001 in 1000000 Avg age of onsetAvg age of onset: 2.5 yrs old, older reported: 2.5 yrs old, older reported Unique predisposition to uncontrolled infection with Unique predisposition to uncontrolled infection with Epstein Epstein

Barr virusBarr virus EBV inducesEBV induces- fatal/severe infectious mononucleosisfatal/severe infectious mononucleosis- Secondary agammaglobulinemiaSecondary agammaglobulinemia- LymphomaLymphoma- Bone marrow failureBone marrow failure Defect in SAP- loss interferes with NK and CD8+ CTL functionDefect in SAP- loss interferes with NK and CD8+ CTL function

Defects in phagocytes Defects in phagocytes generally associated with generally associated with recurrent or severe/ unusual recurrent or severe/ unusual pyogenic infectionspyogenic infections

S.aureus, Serratia, Burkholderia, Nocardia, chromobacterium, fungi (esp, S.aureus, Serratia, Burkholderia, Nocardia, chromobacterium, fungi (esp, Aspergillus)Aspergillus)

Tend to occur at interfaces between host and Tend to occur at interfaces between host and environment-skin, environment-skin, respiratory, Gl or GU tractsrespiratory, Gl or GU tracts

Failure to killFailure to kill organism results in localized infection organism results in localized infection and abscess (and abscess (CGDCGD))

Failure to mobilizeFailure to mobilize WBCs to tissues ( WBCs to tissues (LADLAD,,Chediak- Chediak- HigashiHigashi) may result in rapid spread of infection ) may result in rapid spread of infection systemicallysystemically

Defects in PhagocytesDefects in Phagocytes

Chronic Granulomatous Disease (CGD)Chronic Granulomatous Disease (CGD) ––

1: 2000001: 200000 Due to Due to genetic deficencies in NADPH oxidasegenetic deficencies in NADPH oxidase for neutrophil for neutrophil

oxidative burst required for intracellular killingoxidative burst required for intracellular killing X-linked most common X-linked most common (65-70%) also AR(65-70%) also AR Mean ageMean age of presentation 0-8 yrs,older age possible of presentation 0-8 yrs,older age possible InfectionsInfections with catalase positive organaims with catalase positive organaims (S.aureus, B.Cepacis, S.marcescens, aspergillus app.,Nocardia app)(S.aureus, B.Cepacis, S.marcescens, aspergillus app.,Nocardia app)

GranulomatousGranulomatous inflammation-lymphadenitis,osteomyelitis, inflammation-lymphadenitis,osteomyelitis,

visceral abscess, pneumoniavisceral abscess, pneumonia ProphylaxisProphylaxis with TMP-SMX,IFN- with TMP-SMX,IFN-үү,Itraconazole,Itraconazole


Leukocyte adhesion deficiencyLeukocyte adhesion deficiency- Failure of neutrophil adhesion and migrationFailure of neutrophil adhesion and migration

to site of infection due to to site of infection due to defect in CD18 (LAD1)defect in CD18 (LAD1)- NeutrophillaNeutrophilla, recurrent life-threatening infections, little , recurrent life-threatening infections, little

inflammation at site of inlectioninflammation at site of inlection- Delayed cord separationDelayed cord separation, , severe periodontal diseasesevere periodontal disease Myeloperoxidase deficiencyMyeloperoxidase deficiency- Failure to generale hypochlorous acid in neutrophil,ARFailure to generale hypochlorous acid in neutrophil,AR- Most common Most common inherited neutrophil disorderinherited neutrophil disorder- Rarely develop serious infection-diabetics at risk for fungal Rarely develop serious infection-diabetics at risk for fungal

infectionsinfections


Chediak-Higashi syndromeChediak-Higashi syndromeARAR, results in abnormal neutrophil granule , results in abnormal neutrophil granule formation-formation-abnormal chemotaxis abnormal chemotaxis and and degranulation degranulation with delayed killingwith delayed killingRecurrent cutaneous and respiratory infections, Recurrent cutaneous and respiratory infections, progresses to progresses to malignancymalignancy IRAK4 deficiencyIRAK4 deficiencyImportant signaling molecule in Important signaling molecule in Toll-like Toll-like receptor4 pathwayreceptor4 pathway in macrophages in macrophagesDeficiency leads to recurrent, life-threatening Deficiency leads to recurrent, life-threatening staphylococcal and pnemococcal infectionsstaphylococcal and pnemococcal infections


Hyper-IgHyper-IgEE syndrome (Job syndrome) syndrome (Job syndrome) - - Classified as a Classified as a phagocytic disorderphagocytic disorder, but most likely , but most likely

represents represents an abnormality of T cell an abnormality of T cell function(dysregulated function(dysregulated cytokine & Igcytokine & IgEE production) production)

- - Candida infections,occult infections due to pneumocystis, Candida infections,occult infections due to pneumocystis, cryptocoocuscryptocoocus

- - Recurrent pyogenic infectionsRecurrent pyogenic infections with massively with massively elevated Igelevated IgEE levelslevels

- - Recurrent sinopulmonary infections, Recurrent sinopulmonary infections, pneumatocelespneumatoceles, , severe atopic dermatitissevere atopic dermatitis

- - S.aureusS.aureus most common pathogen most common pathogen


Defects in complementDefects in complement system system lead to susceptibility lead to susceptibility to to encapsulatedencapsulated organisms ( organisms (S.pneumoniaeS.pneumoniae, , N.meningitidisN.meningitidis) & ) & autoimmunityautoimmunity (SLE) (SLE)

Classical pathway:Classical pathway:- Activated by IgE, IgM, CRP bound to a microbeActivated by IgE, IgM, CRP bound to a microbe MBL pathway:MBL pathway:- Activited by mannan binding lectin bound to a microbeActivited by mannan binding lectin bound to a microbe Alternative pathway:Alternative pathway:- Fluid phase activation, amplified on microbeFluid phase activation, amplified on microbe

Defects in Defects in ComplementComplement

Early classical complement deficiencies:Early classical complement deficiencies:- May be associated with May be associated with recurrent pyogenic infections recurrent pyogenic infections and or and or collagen collagen

vascular disease(SLE)vascular disease(SLE) Alternative pathway deficiencies:Alternative pathway deficiencies:- C3-C3- collagen vascular disease and significant infections with encapsulated collagen vascular disease and significant infections with encapsulated

bacteria bacteria - Properdin deficiencyProperdin deficiency-X-linked, fulminanl/ fatal infections due to a -X-linked, fulminanl/ fatal infections due to a

N.meningitidisN.meningitidis MBL deficiency:MBL deficiency:- AutoimmuneAutoimmune, worse prognosis for other infections(AIDS), , worse prognosis for other infections(AIDS),

immunosuppressed patients, liver transplantsimmunosuppressed patients, liver transplants Terminal component deficiencies:Terminal component deficiencies:

- Associated with - Associated with infections due to infections due to N.meningitidisN.meningitidis and and N.gonorrheae, chronic N.gonorrheae, chronic meningococcemlameningococcemla

Defects in ComplementDefects in Complement

Lack of synthesis:Lack of synthesis:

- - Severe liver dysfunctionSevere liver dysfunction Increased consumption:Increased consumption:

- - Immune complex mediated (SLE)Immune complex mediated (SLE)

DIC, endocarditis, disseminated gonococcal infection, DIC, endocarditis, disseminated gonococcal infection, hepatitishepatitis

- - Some glomerulonephritides- C3 nephritic factor causes Some glomerulonephritides- C3 nephritic factor causes C3 depletionC3 depletion

Loss:Loss:

- - Nephrotic syndromeNephrotic syndrome

Complement- Acquired Def.Complement- Acquired Def.

Medical historyMedical history

Physical examinationPhysical examination

Laboratory testingLaboratory testing

Diagnosis of Primary ImmunodeficiencyDiagnosis of Primary Immunodeficiency

Primary Immunodeficiency: Primary Immunodeficiency: InfectionsInfections

Birth to 3 monthsBirth to 3 months– Phagocytic cell defectsPhagocytic cell defects– Complement defectsComplement defects– DiGeorge syndromeDiGeorge syndrome

3 to 6 months3 to 6 months– Severe combined immunodeficiency (SCID)Severe combined immunodeficiency (SCID)

6 to 18 months6 to 18 months– X-linked agammaglobulinemiaX-linked agammaglobulinemia

18 months through adulthood18 months through adulthood– Common variable immunodeficiencyCommon variable immunodeficiency– Complement defectsComplement defects

Diagnosis of Primary ImmunodeficiencyDiagnosis of Primary Immunodeficiency History of SymptomsHistory of Symptoms

Growth measurementsGrowth measurements

Inspection of tonsilsInspection of tonsils

Palpation of lymph nodesPalpation of lymph nodes

OrganomegalyOrganomegaly

Skin lesionsSkin lesions

Diagnosis of Primary Immunodeficiency Diagnosis of Primary Immunodeficiency

Physical ExaminationPhysical Examination

Antibody mediated immunityAntibody mediated immunity– Quantitative immunoglobulinsQuantitative immunoglobulins– IgG subclass determinationIgG subclass determination– IsohemagglutininsIsohemagglutinins

T-cell immunityT-cell immunity– Total lymphocyte countTotal lymphocyte count– Lateral chest x-ray (infants)Lateral chest x-ray (infants)– Delayed hypersensitivity skin Delayed hypersensitivity skin

tests (individuals >2 years of tests (individuals >2 years of age)age)

Diagnosis of Primary Immunodeficiency Diagnosis of Primary Immunodeficiency

Screening TestsScreening Tests

NeutrophilNeutrophil– White blood cell count and White blood cell count and

differentialdifferential ComplementComplement

– Total hemolytic complement Total hemolytic complement test (CH50)test (CH50)

– C3 and C4 concentrationC3 and C4 concentration


Screening TestsScreening Tests

Advanced TestsAdvanced Tests


Management of PIDManagement of PID

General treatmentGeneral treatment

Replacement therapyReplacement therapy

Immune reconstructionImmune reconstruction

Gene therapyGene therapy

General Management of PIDGeneral Management of PID DietDiet Avoidance of pathogens Avoidance of pathogens (“germ-free” care)(“germ-free” care) AntibioticsAntibiotics

- use in acute illness- use in acute illness

- Prophylactic- Prophylactic Avoid whole blood Avoid whole blood transfusion in combined transfusion in combined

immunodeficiency disorder (GVHR)immunodeficiency disorder (GVHR) Avoid live virus Avoid live virus vaccines and BCGvaccines and BCG

Immunoglobulin replacementImmunoglobulin replacement

Treatment of severe antibody disordersTreatment of severe antibody disorders

IVIG 400~ 600 mg/kg/m iv dripIVIG 400~ 600 mg/kg/m iv drip

SCIGSCIG

Frozen plasma 10ml/kg/monthFrozen plasma 10ml/kg/month

CautionCaution : :

with administration of blood productswith administration of blood products if if

selective IgA deficiencyselective IgA deficiency

Specific treatment for cellular deficiencySpecific treatment for cellular deficiency Bone marrow transplantationBone marrow transplantation

Replacement therapyReplacement therapy

- Enzyme replacement- Enzyme replacement

- Gene therapy- Gene therapy

- Thymic hormones- Thymic hormones

- Cytokines- Cytokines

Fetal thymus transplantationFetal thymus transplantation

Interferon gammaInterferon gamma for CGD for CGD

Granulocyte transfusionGranulocyte transfusion

THANKS

متشكرم

An overview of primary immunodeficiency diseases 2014

Documents

Transcript of An overview of primary immunodeficiency diseases 2014