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PRIMARY IMMUNE DEFICIENCY
DISEASESCherrie Anne T. Sierra, MD
INTRODUCTIONImmune System- defense mechanisms to protect the host from
microbes and their virulence factors]• 3 Key Properties:1. highly diverse antigen receptors 2. immune memory3. immunologic tolerance
1. Innate Immune System - rapid triggering of inflammatory responses - all cell lineages
2. Adaptive Immune System- mediated by T and B lymphocytes- antigen-presenting cells
2 Major Components
Primary Immunodeficiency (PID)- expression or function of gene products is
genetically impaired - Mendelian inheritance- overall prevalence of PIDs ~ 5 per 100,000
individuals - combination of recurrent infections, inflammation
and autoimmunity
- presence of recurrent or unusually severe infections
- detailed personal and family medical history genetic tests – Definitive Diagnosis
Classification of Primary Immune Deficiency Diseases
Tests Most Frequently Used to Diagnose PID
Differentiation of phagocytic cells and related PID
Deficiency of the Innate System1. Severe Congenital Neutropeniaimpaired neutrophil counts (<500 /L of blood)absence of puspremature cell death of granulocyte precursors
Diaqnosis:- bone marrow (block in granulopoiesis at the
promyelocytic stage
Treatment:- hygiene- trimethoprim/sulfamethoxazole- SQ injection (G-CSF
2. Aspleniainfections by encapsulated bacteria
Diagnosis:- abdominal UTZ- Howell-Jolly bodies
Treatment:- oral penicillin - vaccination
3. Leukocyte Adhesion Deficiency (LAD)
a. LAD I- Most common- caused by mutations in the 2 integrin gene
b. LAD II- extremely rare - defect in selectin-mediated leukocyte c. LAD III- defect in a regulatory protein- can develop bleeding- causes impaired wound healing and delayed loss of
the umbilical cord
• pus-free skin/tissue infections and massive hyperleukocytosis (>30,000/L)
• Diagnosis:- Immunofluorescence Treatment:- Hematopoietic Stem Cell Transplantation (HSCT)
4. Chronic Granulomatous Diseases- impaired phagocytic killing of microorganisms by
neutrophils and macrophages - incidence is approximately 1 per 200,000 live
births- causes deep-tissue bacterial and fungal abscesses
in macrophage-rich organs
Infectious Agents:-Staphylococcus aureus and Serratia
marcescens
-Burkholderia cepacia
- Fungi (Aspergillus)
- defective production of reactive oxygen species in the phagolysosome membrane
- results from the lack of a component of NADPH oxidase
Treatment:- trimethoprim/sulfamethoxazole- Daily administration of azole derivatives (intraconazole)- HSCT
5. Mendelian Susceptibility to Mycobacterial Disease - defect in the IL-12 interferon (IFN) leading to
impaired IFN--dependent macrophage activation- Tuberculous & nontuberculous mycobacteria --
Hallmark- prone to developing Salmonella infections- Treatment: interferon
6. Toll-Like Receptor (TLR) Pathway Deficiencies- specific susceptibility to herpes simplex
encephalitis- Susceptibility to both invasive, pyogenic infections
and mycobacteria
7. Complement Deficiency
- composed of plasma proteins that leads to the deposition of C3b fragments- deficiency in classic pathway (C1q, C1r, C1s, C4,
and C2) can predispose an individual to bacterial
Diagnosis:- functional assays (CH50 and AP50 tests) Treatment:- daily administration of oral penicillin
PRIMARY IMMUNODEFICIENCIES OF THE ADAPTIVE IMMUNE SYSTEM
(T Lymphocyte Deficiencies)
PRIMARY IMMUNODEFICIENCIES OF THE ADAPTIVE IMMUNE SYSTEM
1. SEVERE COMBINED IMMUNODEFICIENCIES- complete absence of these cells (block in T cell
development) - estimated to be 1 in 50,000 to 100,000 live birthsClinical Manifestations:- recurrent oral candidiasis- failure to thrive- protracted diarrhea - acute interstitial pneumonitis caused by Pneumocystis jiroveci
Diagnosis:- Lymphocytopenia - - absence of a thymic shadow on a chest x-ray - determination of the number of circulating T, B,
and NK lymphocytes– (Accurate Diagnosis)
• Mechanisms:a. Cytokine-Signaling Deficiency- most frequent SCID phenotype - absence of both T and NK cells
b. Purine Metabolism Deficiency- deficiency in adenosine deaminase (ADA) - induce premature cell death of lymphocyte
progenitors - cause bone dysplasia with abnormal
costochondral junctions and metaphyses and neurologic defects
c. Defective Rearrangements of T and B Cell Receptors- selective deficiency in T and B lymphocytes - account for 20-30% of SCID - Can cause developmental defects
d. Defective (Pre-)T Cell Receptor Signaling in the Thymus- deficiencies in CD3 subunits associated with the
(pre)TCR and CD45
e. Reticular Dysgenesis- causes T and NK deficiencies with severe
neutropenia and sensorineural deafness- results from an adenylate kinase 2 deficiency
f. Defective Egress of Lymphocytes
- very low T cell counts- result from a deficiency in coronin-1ATreatment:- anti-infective therapies- immunoglobulin replacement- parenteral nutrition support- HSCT- a pegylated enzyme
THYMIC DEFECTS
- profound T cell defecta. DiGeorge syndrome
-constellation of developmental defects-thymus is completely absent
Diagnosis - Immunofluorescence (hemizygous deletion in the long arm of chromosome 22)
b. CHARGE -coloboma of the eye, heart anomaly, choanal atresia, retardation, genital and ear anomalies syndrome Treatment: thymic graft
OMENN SYNDROME- erythrodermia, alopecia, hepatosplenomegaly and
failure to thrive- T cell lymphocytosis, eosinophilia, and low B cell
countTreatment: HSCT
FUNCTIONAL T CELL DEFECTS - partially preserved T cell differentiation - Causes chronic diarrhea and failure to thrive - Diagnosis:- Phenotyping - in vitro functional assays
a. Zeta-Associated Protein 70 (ZAP70) Deficiency
- complete absence of CD8+ T cells
b. Calcium Signaling Defects- defective antigen receptor-mediated Ca2+ influx- prone to autoimmune manifestations (blood
cytopenias) and nonprogressive muscle disease
c. Human Leukocyteantigen (HLA) Class II Deficiency- low but variable CD4+ T cell counts - defective antigen-specific T and B cell responses- susceptible to herpesvirus, adenovirus and
enterovirus infections and chronic gut/liver Cryptosporidium infections
d. HLA Class I Deficiency- reduced CD8+ T cell counts- loss of HLA class I antigen expression- cause chronic obstructive pulmonary disease and
severe vasculitis
T CELL PRIMARY IMMUNODEFICIENCIES WITH DNA
REPAIR DEFECTS
a. Ataxia-Telangiectasia (AT) - autosomal recessive disorder - causes B cell defects - progressive T cell immunodeficiency- hallmark features: telangiectasia and cerebellar
ataxia- young children with IgA deficiency
Diagnosis:- cytogenetic analysis (chromosomes 7 and 14)Treatment: immunoglobulin replacement
b. Nijmegen Breakage Syndrome (NBS)- severe T and B cell combined immune deficiency
with autosomal recessive inheritance- exhibit microcephaly and a bird-like face- risk of malignancies is very high- deficiency in Nibrin caused by hypomorphic
mutations
c. Dyskeratosis Congenita (Hoyeraal-Hreidarsson Syndrome)- absence of B and NK lymphocytes- progressive bone marrow failure, microcephaly, in
utero growth retardation and gastrointestinal disease
d. Immunodeficiency with Centromeric and Facial Anomalies (ICF) - mild T cell immune deficiency with a more severe
B cell immune deficiency- Features: coarse face, digestive disease, and mild
mental retardationDiagnostic:- cytogenetic analysis
T CELL PRIMARY IMMUNODEFICIENCIES WITH HYPER-
IGE
- elevated serum IgE levels Autosomal Recessive Hyper-IgE Syndrome - T and B lymphocyte counts are low- recurrent bacterial infections in the skin and
respiratory tract - pox viruses and human papillomaviruses
AUTOSOMAL DOMINANT HYPER-IGE SYNDROME (HIES)
- mutation in the gene encoding the transcription factor STAT3
- combination of recurrent skin and lung infections complicated by pneumatoceles
- caused by pyogenic bacteria and fungiFeatures: - facial dysmorphy, defective loss of primary teeth,
hyperextensibility, scoliosis, and osteoporosis- Elevated serum IgE levels
CARTILAGE HAIR HYPOPLASIA
- caused by mutations in the RMRP gene for a noncoding ribosome-associated RNA
- short-limb dwarfism, metaphyseal dysostosis and sparse hair
- can predispose to erythroblastopenia, autoimmunity, and tumors
B cell differentiation and related primary immunodeficiencies (PIDs)
CD40 LIGAND AND CD40 DEFICIENCIES
- B cell immune deficiency - leads to profound deficiency (IgG, IgA, and IgE)- prone to opportunistic infections (interstitial
pneumonitis), cholangitis (Cryptosporidium) and infection of the brain (Toxoplasma gondii)
WISKOTT-ALDRICH SYNDROME
- incidence of approximately 1 in 200,000 live births- caused by mutations in the WASP gene - relative CD8+ T cell deficiency with low serum IgM
levels and decreased antigen-specific antibody responses
- clinical manifestations: recurrent bacterial infections, eczema, and bleeding
- Complications: bronchopulmonary infections, viral infections, severe eczema, autoimmune manifestations, lymphoma
- Thrombocytopenia can be severe- typical feature: reduced-sized platelets on a blood
smear
Diagnosis: intracellular immunofluorescence analysis of WAS protein
Treatment:- Prophylactic antibiotics, immunoglobulin G (IgG) supplementation, topical treatment of eczema- splenectomy improves platelet count - Allogeneic HSCT is curative
B Lymphocyte Deficiencies
- account for 60-70% of all cases- B lymphocytes antibodies: IgM, IgG, IgADefective antibody production results to:- invasive, pyogenic bacterial infections- recurrent sinus and pulmonary infections
(Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis)
- Parasitic infections (Giardia lambliasis) bacterial infections (Helicobacter and Campylobacter) of the gut
- infections rarely occur before the age of 6 monthsDiagnosis: - determination of serum Ig levels- Determination of antibody production - B cell phenotype determination in switched and
nonswitched memory B cells
AGAMMAGLOBULINEMIA
- complete lack of antibody production - mutation in the BTK gene - severe, chronic, disseminated enteroviral
infections - Diagnosis: examination of bone marrow B cell
precursors- Treatment: immunoglobulin replacement
HYPER-IGM (HIGM) SYNDROMES
- characterized by defective Ig CSR- results in very low serum levels of IgG and IgA and
elevated or normal serum IgM levels- have enlarged lymphoid organs- result from fetal rubella syndromeDiagnosis:- screening for an X-linked CD40L deficiency and an
autosomal recessive CD40 deficiency
COMMON VARIABLE IMMUNODEFICIENCY (CVID)
- characterized by low serum levels of one or more Ig isotypes
- prevalence is estimated to be 1 in 20,000- develop lymphoproliferation (splenomegaly), granulomatous lesions, colitis, antibody-mediated autoimmune disease, and lymphomas
Diagnosis:- should exclude the presence of hypomorphic mutations associated with agammaglobulinemia or more subtle T cell defects
SELECTIVE IG ISOTYPE DEFICIENCIES
- IgA deficiency -- most common - increased numbers of acute and chronic
respiratory infections (bronchiectasis) - increased susceptibility to drug allergies, atopic
disorders, and autoimmune diseases - IgA deficiency may progress to CVIDTreatment: immunoglobulin replacement
SELECTIVE ANTIBODY DEFICIENCY TO POLYSACCHARIDE ANTIGENS
- prone to S. pneumoniae and H. influenzae infections of the respiratory tract- Defective production of antibodies against polysaccharide antigens - a defect in marginal zone B cells, a B cell subpopulation involved in T-independent antibody responses
IMMUNOGLOBULIN REPLACEMENT
-IgG antibodies have a half-life of 21-28 daysTreatment:- injection of plasma-derived polyclonal IgG (repeated every 3-4 weeks, with a residual target level of 800 mg/mL in patients who had very low IgG level)- Immunoglobulin replacement can be performed by IV or
subcutaneous routes (800 mg/mL once a week)--lifelong therapy
main goal is to reduce the frequency of the respiratory tract infections and prevent chronic lung and sinus disease
PRIMARY IMMUNODEFICIENCIES AFFECTING REGULATORY
PATHWAYS
a. Hemophagocytic Lymphohistiocytosis- unremitting activation of CD8+ T lymphocytes and
macrophages that leads to organ damage (liver, bone marrow, and CNS)
- results from impair T and NK lymphocyte cytotoxicity
- EBV is the most frequent trigger
Clinical Features:- fever, hepatosplenomegay, edema, neurologic
diseases, blood cytopenia, increased liver enzymes, hypofibrinogenemia, high triglyceride levels, elevated markers of T cell activation
Diagnosis:- Functional assays of postactivation cytotoxic
granule exocytosis The conditions can be classified into three
subsets:1. Familial HLH with autosomal recessive inheritance, including perforin deficiency
2. HLH with partial albinism- hair examination can help in the diagnosis- Chediak-Higashi syndrome, Griscelli syndrome, and Hermansky Pudlak syndrome type II
3. X-linked proliferative syndrome (XLP) - induction of HLH following EBV infection- May develop progressive
hypogammaglobulinemia- life-threatening complicationTreatment: -immunosuppression (cytotoxic agent VP-16 or anti-T cell antibodies)- HSCT
Autoimmune Lymphoproliferative Syndrome
- nonmalignant T and B lymphoproliferation- caused by a defect in Fas-mediated apoptosis of
lymphocytes- causing splenomegaly and enlarged lymph nodes- Hallmark: CD4 -CD8- TCR+ T cells (20-50%)
- 70% of patients also display autoimmune manifestations (autoimmune cytopenias, Guillain-Barre syndrome, uveitis, and hepatitis)
Treatment: pro-apoptotic drugs
Colitis, Autoimmunity, and Primary Immunodeficiencies
- Several PIDs can cause severe gut inflammationa. Immunodysregulation Polyendocrinopathy Enteropathy X-linked Syndrome (IPEX)- caused by loss-of-function mutations in the gene
encoding the transcription factor FOXP3- widespread inflammatory enteropathy, food
intolerance, skin rashes, autoimmune cytopenias and diabetes
Treatment: allogeneic HSCT
b. Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dysplasia (APECED) Syndrome- mutations in the autoimmune regulator (AIRE)
gene- Candida infection is often associated with this
syndrome
CONCLUSION
important to raise awareness of these diseasesearly diagnosis is essential for establishing an
appropriate therapeutic regimen A precise molecular diagnosis is not only
necessary for initiating the most suitable treatment but it is also important for genetic counseling and prenatal diagnosis
Thank You