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

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