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Chapter 24: Primary Immunodeficiency Diseases

Immunodeficiency

  • Primary Immune deficiency disease - heritable, genetic defect

    • Disorders that affect both cellular and humoral components (combined)

    • Defects of antibody production (antibody deficiency syndrome)

    • Disorders of innate immunity

  • Secondary Immune deficiency - consequence of another pathologic process such as infection, malignancy, malnourishment or iatrogenic

Combined Immunodeficiencies

  • impaired development and function of T lymphocytes

  • Development of B or natural killer (NK) lymphocytes (or both) is also affected

Severe Combined Immunodeficiency (SCID)

  • Genetically heterogeneous group with profound T-cell developmental failure ⇒ functional absence of cellular & humoral immunity.

  • Clinical picture

    • Susceptible to opportunistic infections with commensal organism that are normally nonpathogenic such as Pneumocystis jiroveci, even attenuated vaccine organisms can cause severe infection (oral polio, rotavirus, varicella and BCG)

    • Recurrent severe infections beginning within \leq 3 months (though placental IgG may delay).

    • Common organisms: mucocutaneous Candida, common viruses (varicella, CMV, RSV, influenza, parainfluenza), opportunists (Pneumocystis jiroveci), vaccine strains (OPV, BCG).

    • Non-infectious: chronic diarrhoea, failure to thrive, dermatitis/erythroderma, auto-immunity, EBV-driven malignancy.

    • Autoimmunity and other manifestations of immune dysregulation are frequently observed

  • Classification is traditionally by blood lymphocyte phenotype:

    • T^-B^-NK^-

    • T^-B^-NK^+

    • T^-B^+NK^-

    • T^-B^+NK^+
      (maternal T-cell engraftment in \approx 40\% may confound).

T^-B^-NK^- SCID (ADA, AK2, NP genes)

  • Adenosine Deaminase (ADA) deficiency

    • Accounts for 10\text{–}15\% of SCID; autosomal recessive.

    • Pathogenesis: ADA absence ⇒ ↑ deoxyadenosine → \uparrow \text{dATP} ⇒ ribonucleotide-reductase inhibition ⇒ halted DNA synthesis + apoptosis (T cell precursor in thymus >> B).

      • leads to intracellular accumulation of deoxyadenosine

      • B cell more often depleted than in PNP deficiency

    • Phenotype: profound T, B, NK lymphopenia, bone defects, sensorineural deafness, liver disease, lung disease resembling alveolar proteinosis, neurologic delay, auto-immunity.

    • Immune dysregulation is more common and manifests with allergy (eczema, asthma) and autoimmunity (cytopenias, hypothyroidism, diabetes)

    • Omenn Syndrome - may present with generalized erythroderma and infiltration of the skin by activated autologous T cells

    • BMA: hypocellular; myelodysplasia have been reported

    • Increased risk for multicentric dermatofibrosarcoma protuberans - rare tumor, chrom translocatio t(17;22) resulting in COLIA-platelet derived growth factor β (PDGFB) fusion gene

    • Autoimmunity is common in patients with residual ADA enzyme activity

    • Therapeutics:
      • HSCT ‑ best with matched sibling (survival >85\%).
      • Enzyme-replacement PEG-ADA (weekly IM).
      • Gene therapy (γ-retro/lentiviral + low-dose busulfan) → durable immune output but often sub-normal CD3^+ counts.

  • Purine Nucleoside Phosphorylase (PNP) deficiency

    • \approx 70 cases worldwide; mainly cellular defect (+ neurologic 50\%).

    • Very low T; B and serum Ig levels initially normal then decline; reduced serum and urine urate levels, uric acid ↓.

    • leads to intracellular accumulation of doxyguanosine; required for production of hypoxanthine, a precursor of uric acid

    • Susceptible to viral and fungal infection

    • Neurologic complications - spasticity, diplegia, paresis, and other motor disorders, as well as cognitive impairment

    • Autoimmune manifestations such as cytopenias are very common

    • Only curative: HSCT.

  • Diagnosis: meaasurement of ADA and PNP activity in red blood cell or leukocyte lysates

  • Prenatal diagnosis - cultured amniotic fluid or chorionic villus cells or on fetal blood sampling

  • Reticular Dysgenesis (AK2 deficiency)

    • AR; AK2 regulates levels of ADP in mitochondria

    • Severe agranulocytosis (block at the promyelocyte stage) + sensorineural deafness; apoptosis from mitochondrial ADP dysregulation; NK cells differentiation is usually preserved

      • OS with oligoclonal expansion of T cells with AK2 hypomorphic (partially functional) mutations

    • Increased risk of myelodysplasia

    • HSCT needed; myeloablation required, outcome poorer.

T^-B^-NK^+ SCID

  • Defects of Recombination-activating genes (RAG1, RAG2)

    • RAG1 and RAG2 encode DNA binding proteins that bind to specific recognition sequences flanking coding gene elements of the Ig and T cell receptor (TCR) loci

    • Very low numbers of T and B lymphocytes but NK cell differentiation is preserved

    • Leaky or atypical SCID - differentiation of a limited number of T and less frequently B cells; hypomorphic RAG1 or RAG2 mutations and acquire oligoclonal activated CD45RO+ phenotype

      • Omenn Syndrome - clinical features suggestive of aGVHD; recurrent severe infections, failure to thrive, chronic severe diarrhea and erythroderma with exfoliation and exudation

      • PE: hepatosplenomegaly and lymphadenopathy; anemia, hypogammaglobulinemia with elevated IgE level, decrease peripheral B cells and presence of activated CD45RO+

      • Thymic biopsy: abnormalities of medullary epithelial cells with impaired expression of AIRE (autoimmune regulator) and absence of FOXP3+ cells

        • AIRE - permit intrathymic deletion of autoreactive T cells or their diversion to FOXP3+ regulatory T cells

    • Environmental triggers (e.g., parainfluenza-3, CMV) or somatic reversions may modulate.

  • Artemis (DCLRE1C) deficiency

    • AR; mutations in the gene DCLRE1C - critical role in the function of NHEJ or repair of double-stranded DNA breaks

    • General radiation sensitivity, oral/genital ulcers, dental anomalies and malabsorption

    • Partial form - increased risk of lymphoma

  • DNA Ligase IV Deficiency

    • LIG4 mutation

    • Microcephaly, cognitive impairment, BMF and cellular immunodeficiency

    • Profound cellular radiosensitivity; increased risk for MDS and Leukemia

  • Cernunnos Deficiency /XLF (NHEJ1)

    • NHEJ1 gene mutation; less severe

    • Lymphopenia, radiation sensitivity, growth retardation, microcephaly and developmental delay, BMF

    • Increased risk for MDS

  • DNA-PKcs (PRKDC)

    • Homoxygous missense mutation in the PRKDC gene

    • Cellular radiosensitivity but without microcephaly or mental retardation

T^-B^+NK^- SCID

  • X-linked SCID

    • IL2RG (γc) mutations (≈ 40\% of Western SCID).

    • Lacks T and NK lymphocytes - defective signaling in IL-7R and IL-15R; B lymphocytes are present but nonfunctional due to impaired IL-21 mediated signaling

    • Signature susceptibility to chronic and severe HPV

    • May not be corrected with HSCT

  • JAK3 deficiency

    • autosomal recessive – clinically identical to X-SCID; defects in tyrosine kinase JAK3

    • Hypomorphic mutations - residual JAK3 expression with partial preservation of circulating T cells and delayed clinical onset with lymphoproliferation and susceptibility to warts and other viral infections

T^-B^+NK^+ SCID

  • Defects in the IL7Rα chain

    • IL7R gene mutations – absence of T lineage with normal B/NK; occasional OS.

  • TCR/CD3 complex (CD3D, E, Z) defects – variable severity; normal-sized thymus noted in

  • Defects in CD3δ (CD3D gene)

    • varying degrees of panhypogammaglobulinemia, susceptible to disseminated viral infection

    • Normal sized thymus noted

  • Defects in CD3E

    • CD3E and CD3Z mutations

    • Associated with markedly reduced levels of TCR/CD3 complex on the surface of circulating T lymphocytes

    • Recurrent infections and autoimmunity

  • CD45 (PTPRC) deficiency

    • Mutations in PTPRC gene encoding CD45

    • Diminished numbers of poorly functional T cells, normal or increased numbers of B cells and variable number of NK cells

  • RHOH deficiency

  • LCK deficiency

    • produce atypical combined immunodeficiency with relative subset deficiencies.

MHC Class II Deficiency

  • HLA class II - restricted to specialized APCs, including monocytes and macrophages, dendritic cells, and B cells but are also expressed by thymic epithelial cells; mainly present peptides imported from outside the cell to antigen receptors of T cells bearing CD4

  • Present early in life with recurrent and severe infections, chronic diarrhea and failure to thrive

  • Chronic opportunistic infections of the GI tract caused by Cryptosporidium or CMV may lead to severe liver disease with sclerosing cholangitis

  • Markedly decreased number of circulating CD4+ cells and delayed hypersensitivity responses are impaired

  • Defective regulation of gene transcription as a result of four different genes (CIITA, RFXANK, RX5, RFXAP)

  • Do not survive without HSCT

Defective expression of HLA Class I

  • mutation in either TAP1 or TAP2 or the gene encoding tapasin

  • Main immunologic abnormality is low peripheral blood CD8+ T cells; antibody responses may be normal

  • Upper and lower respiratory tract bacterial infections, bronchiectasis, and granulomatous skin inflammation

ZAP-70 Deficiency

  • Severe, early onset infections, almost complete absence of CD8+ T cells

  • CD4+ cells appear normal but fails to respond to signals delivered by way of TCR

  • Immune dysregulation, skin rash, wheezing and eosinophilia

  • Tx is HSCT

CD8α Deficiency

  • CD8α2 or CD8αβ; gene CD8A, AR disorder

  • Lack circulating CD8+ lymphocytes, increased CD3+CD4-CD8- cells that express markers of effector cytotoxic T lymphocytes (CD11b, CD57); recurrent respiratory infections

Macrophage Stimulating 1 Deficiency

  • MST1 or serine threonin kinase 4 (STK4) - controls apoptosis and survival of naive T cells by inducing expression of FOXO1

  • Recurrent infections, immune dysregulation, moderate degree of neutropenia, and congenital heart disease

  • Viral infections are common, warts, molluscum contagiosum, and EBV-driven lymphoproliferative disease

  • Naive T cells are markedly decreased; expansion of TEMRA cells; increased apoptosis and reduced proliferation to mitogens

  • Increased proportion of of transitional B lymphocytes with reduced number of memory B cells

Dedicator of Cytokinesis 8 Deficiency

  • DOCK8 mutation, AR form of combine immunodeficiency with hyperIgE (HyperIgE syndrome type 2)

  • Chronic viral cutaneous infections (warts, molluscum contagiosum), recurrent skin abscesses and cellulitis, respiratory tract infections, candidiasis, eczema

  • Severe allergy, autoimmunity (cytopenias, CNS vasculitis) and increased risk of malignancy (Epithelial cell carcinoma, lymphomas, leiomyosarcoma)

  • Severe prognosis, high mortality; tx: HSCT

Coronin-1A Deficiency

  • Coronin-1A - inhibits F-actin formation in T lymphocytes, modulates cytoskeleton rearrangements and T cell activation

  • Combined immunodeficiency with recurrent and severe infections including severe varicella and EBV driven lymphoproliferation

  • Developmental delay and profound T cell lymphopenia

  • Tx: HSCT

VOD with immunodeficiency

ID caused by defects of calcium release activated channels

Magnesium transporter protein 1 deficiency

Caspase Recruitment Domain Family Member 11 Deficiency

IL-21 Receptor Deficiency

Management of SCID / Combined ID

  • Diagnostic approach

    • Newborn Screening performed by quantifying levels of TCR excision circles

      • T-cell receptor excision circle (TREC) assay; \text{TRECs} \downarrow or absent in classic SCID.

      • Tandem mass spectrometry - used for newborn screening of ADA deficiency

    • Flow cytometry of naive CD45RA+/CD62L+ vs memory CD45RO+/CD62L-; proliferation to PHA & anti-CD3.

    • Molecular genotyping ⇒ definitive.

  • Infection prophylaxis: IVIG infusions, TMP-SMX, antifungals; CMV-safe irradiated blood.

  • HSCT

    • Pediatric emergency; no conditioning for matched sibling; T-cell depleted haploidentical viable (survival >95\% if <3.5 mo age).

    • Conditioning needed when autologous T present

    • Definitive and mainstay of treatment for the majority

  • Gene therapy

    • ADA-SCID: \uparrow survival, mild lymphoid output.

    • X-SCID: early trials rescued \approx 90\% immunity but 5/20 leukemias due to LTR insertion near \text{LMO2} ⇒ now self-inactivating vectors.

Immunodeficiency Syndromes

Wiskott–Aldrich Syndrome (WAS)

  • Triad: eczema + micro-thrombocytopenia (platelet volume 3.8–5.0\,\text{fL}) + immunodeficiency.

  • X-linked disease; Mutated WAS gene ⇒ defective WASP (cytoskeletal signaling).

  • Spectrum: classical (score \ge 3), “X-linked thrombocytopenia” (residual WASP) milder form of disease, activating mutations ⇒ X-linked neutropenia.

  • Bloody diarrhea - may be the initial feature, eczema may be mild or exuberant; SSI is common

  • Recurrent otitis media and sinopulmonary infections and opportunistic infections are common

  • Autoimmune hemolytic anemia, vasculitis, inflammatory bowel disease, glomerulonephritis and other autoimmune process;

  • Increased risk for EBV positive lymphoma and aortic aneurysm.

  • Dx: WASP expression by flow cytometry or western blotting; mutation analysis is required

  • Immune picture: ↓ T-cell responses to CD3, high \text{IgA/IgE}, low \text{IgM}, ↓ CD27^+ memory B, dendritic podosome defects.

  • Therapy: IVIG, splenectomy discouraged, curative HSCT (>95\% with MSD).

  • Rare: WIP deficiency phenocopies WAS, WIPF1 gene mutation

DiGeorge Syndrome (22q11.2 deletion)

  • Failure of migration of neural crest cells into the 3rd/4th pharyngeal pouches: facies, cardiac defects, parathyroid hormone deficiency - hypocalcemic tetany, variable T-cell deficiency.

  • Complete aplasia ⇒ athymic → needs cultured thymic implant; partial forms improve with age.

  • Facies: hypertelorism, micrognathia, short philtrum; low-set, posteriorly rotated ears with small pinnae

  • Cardiac defects mc: type B interrupted aortic arch; Truncus arteriosus and other conotruncal anomalies

  • Dysphagia 2 to laryngoesophageal dysmotility; bilateral paired parathyroid glands are normally adherent to the thymus

  • Neuropsychiatric problems and cognitive impairment

  • Gene: TBX1; also 10p13 deletions.

  • Complete form: thymus is absent or severely hypoplastic - absent or markedly decreased T lymphocytes; B cells are present but specific antibody production is impaired

  • Atypical complete DGS - oligoclonal activated (CD45RO+) tissue-infiltrating T lymphocytes are detected

  • Auto-immunity (ITP, arthritis), allergy, psychiatric disorders frequent.

  • Severe viral and opportunistic infections are very rare; live viral vaccines may be administered safely

  • Tx: HSCT for matched donor

FOXN1 deficiency

  • FOXN1 - critical role in development of thymus and eccrine glands

  • Cause athymia, profound T cell lymphopenia, alopecia totalis, and nail dystrophy

  • “Human nude” phenotype: alopecia, nail dystrophy, athymia ⇒ profound CD4^+ lymphopenia.

  • Treated by thymus transplant; HSCT from HLA-identical sibling

Ataxia–Telangiectasia (ATM defect)

  • AR; ATM gene mutation - involved in detection of DNA damage and initiation of repair; lymphocytes have remarkable number of chromosomal translocations and inversions

  • Chromosome instability, progressive cerebellar ataxia, conjunctival/ cutaneous telangiectasia, IgA/IgG_{2,4} deficiency, ↑ AFP (>95\%).

  • 30\text{–}40\% malignancy risk; pulmonary failure leading mortality \approx 19\text{–}25 yrs.

  • Increased incidence of lymphoma and sensitive to radiation; marked delay in induction of tumor suppressor p53 and BRCA1 after exposure to radiation

  • Motor impairment is progressive

  • Telangiectases of conjunctival and cutaneous vessels do not appear until children are 3-5yo

  • Cutaneous lesions found mainly on the pinnae and skin creases

  • Immunodeficiency - recurrent sinopulmonary bacterial infections, granulomatous lesions are frequently seen

  • No definitive cure

DNA-repair / Chromosomal-instability IDs

  • Nijmegen Breakage (NBS1), AT-like (MRE11A), PMS2 & MSH6 mismatch repair ⇒ SLE-like, lymphoma.

    • AR inheritance; NBS1 gene involvement

    • Growth retardation, microcephaly, immunodeficiency, sensitivity to radiation and high rate of lymphoma

  • PMS2 deficiency - defective CSR, cafe au lait spots and increased occurrence of malignancies

  • Bloom Syndrome - chromosomal instability associated with increased frequency of infections, low levels of IgM, impaired delayed type of hypersensitivity responses

    • Caused by mutations of BLM gene

  • Immunodeficiency-centrometric instability facial anomalies syndrome (ICF)

    • Hypogammaglobulinemia, facial dysmorphisms and branching of chrom 1,9, and 16

    • Mutations in DNMT3B or in the ZBTB24 gene – dwarfism + hypogammaglobulinemia.

  • Mini chromosome maintenance-deficient 4

    • AR; MCM4 gene mutations ⇒ NK^{dim} absence, recurrent and severe viral infection.

Pigmentary Dilution with cytotoxicity defect

  • Chédiak–Higashi (LYST gene- lysosomal trafficking regulator) - partial albinism, peripheral neuropathy and increased risk of viral infections

    • Neutropenia is often present and may facilitate bacterial infections

    • Giant lysosomes in leukocytes facilitates diagnosis

    • HSCT only definitive treatment

  • Griscelli 2 (RAB27A gene - protein that permits docking of the cytolytic granules to the cell membrane)

    • Partial albinism and immunodeficiency with increased susceptibility to infections, fever, and cytopenia

  • Griscelli 1 MYOSA gene mutation encoding myosin Va protein

  • GS 3 mutation of gene encoding for melanin chaperone melanophilin

    • Hypopigmentation without immunodeficiency

  • Hermansky–Pudlak 2/9 (AP3B1, PLDN) ⇒ partial albinism + HLH-like “accelerated phase”.

    • Occulocutaneous albinism, bleeding diasthesis, neutropenia, interstitial lung disease, and recurrent infection

    • HPS9 - hypopigmentation and nystagmus, recurrent cutaneous infection

NF-κB pathway & Toll-like receptor (TLR) signaling

  • Regulated by an inhibitor IκB phosphorylated by IKK —> IκB degradation and liberates active NF-κB

  • NEMO - IKK subunit, an essential NF-κB modulator;

    • X-linked dominant- incontinentia pigmenti in females

  • Combined immunodeficiency,hyperhidrotic ectodermal dysplasia, and lymphedema with osteoporosis.

  • May suffer opportunistic-type disseminated viral infections and P. jiroveci pneumonia; highly susceptible to atypical mycobacterial infection

  • Inflammatory bowel disease - role in controlling epithelial integrity

  • Hypogammaglobulinemic and impaired response to vaccines (especially to polysaccharide antigens)

  • TX: gamma globulin and antibiotic prophylaxis is essential; HSCT may cure immunologic abnormalities

  • IκBα gain-of-function similar.

  • IRAK4 / MYD88 – invasive pyogenic infection in childhood only (wanes by >10 yrs).

Defects of Toll-like receptor signaling

  • IRAK-4 and Myd88 -have severe, invasive bacterial infections such as meningitis, bacteremia, septic arthritis, deep tissue abscesses, and osteomyelitis with gram-positive organisms (S. Aureus and S. Pneumoniae) in early childhood

  • Routine tests of immune function are normal; high levels of all Ig isotypes

WHIM (CXCR4 dominant)

  • AD; mutations of CXCR4 - prevent interaction with β-arrestin, allowing continuous signaling induced by CXCL12; retains neutrophils in the bone marrow (myelokathexis) and alters trafficking of B and T lymphocytes, causing lymphopenia

  • defective number of plasmacytoid dendritic cells, a major source of IFN-γ cause warts and neutropenia and hypogammaglobulinemia —> recurrent bacterial Infections

  • Treatment: G-CSF, plerixafor (AMD3100, CXCR4 antagonist), IVIG.

Hyper-IgE Syndromes

  • STAT3 dominant-negative (type 1)

    • “Job” Syndrome - severe sinopulmonary bacterial infections, severe skin superinfections with S. Aureus on chronic eczematous eruption

    • Susceptibility to Aspergillus fumigatus pneumonitis with pneumatocele formation.

    • Asymmetric or coarse facial features, delayed shedding of primary teeth, bone fragility and fractures, scoliosis and keratoconjunctivitis

    • cold abscesses (Staph), pneumatoceles, \uparrow\,\text{IgE} (median >3000\,\text{IU}\,\text{mL}^{-1}), Th17 deficiency, bone fractures, aneurysms.

    • Increased rate of malignancies especially NHL

  • DOCK8 deficiency (AR HIES) – severe viral warts, allergies, cancer risk; HSCT curative.

  • TYK2 deficiency – atopy, susceptibility to infections sustained by S.aureus, BCG, Salmonella, viral infections ± \uparrow\,\text{IgE}.

Chronic Mucocutaneous Candidiasis (CMC)

  • Affects nails, skin, and mucosa - clinical hallmark of 3 distinct genetic disorders that affect IL-17-dependent immunity

  • AR deficiency of IL-17 receptor α chain (IL17RA), partial AD IL-17F deficiency and heterozygous gain-of-function mutations of STAT1 - mc cause of isolated CMC

  • CARD9 gene mutation - affect development of Th17 cells and cause CMC; are also at increased risk of disseminated Candida infections as well as other fungal infections

Skeletal-Immuno syndromes

  • Cartilage–Hair Hypoplasia (mutations in RMRP gene) – AR; short-limbed dwarfism with metaphyseal dysplasia, sparse and fair hair, and joint hypermotility

    • Dyserythropoietic anemia and variable degree of immunodeficiency

    • 6-10% rate of malignancies - lymphoma and basal cell carcinoma

    • Tx: HSCT

  • Schimke immuno-osseous dysplasia (SMARCAL1)

    • AR; mutations of SMARCAL1 gene

    • Spondyloepiphyseal dysplasia, focal glomerulosclerosis leading to progressive renal failure and T cell immunodeficiency.

Folate / Cobalamin metabolism IDs

  • TCN2 (transcobalamin II), MTHFD1 mutations, proton-coupled folate transporter that impede folate absorption through the GI mucosa – SCID-like with megaloblastic anemia, leukopenia, atypical HUS and neurologic abnormalities

  • Tx: parenteral supplementation

GATA2 deficiency (MonoMAC Syndrome/ DCML deficiency)

  • Onset in late childhood or adulthood, susceptibility to disseminated nontuberculous mycobacterial disease, recurrent and severe viral infections (HPV and HSV) and fungal infections

  • Increased risk of MDS and malignancies -AML, SCC, and EBV-positive leiomyosarcoma

  • Pulmonary alveolar proteinosis and primary lymphedema

  • Monocytopenia, NK/ B / T/ dendritic depletion, elevated Flt3L levels

  • Prognosis is severe; HSCT curative.

Immune Dysregulation Syndromes

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Syndrome (APECED)

  • AR; AIRE gene mutation (autoimmune regulator) - impairment of central T cell tolerance

  • Triad: autoimmune hypoparathyroidism + Addison disease + CMC

  • Prone to autoimmune manifestations: hepatitis, alopecia, ovarian failure, and hypothyroidism

  • Increased incidence of oral SCC and fulminant autoimmune hepatitis

  • multiple organ auto-immunity; auto-Abs to IFN-α/β, IL-17/22.

Immune Dysregulation Polyendocrinopathy Enteropathy X-linked Syndrome (FOXP3, X-linked)

  • X-linked; FOXP3 gene mutation - controls generation of Treg cells

  • Severe early-onset autoimmune manifestations that involve the gut (intractable diarrhea), pancreas (diabetes), the skin, and other organs, lymphoproliferation and cytopenias.

  • Tx: immunosuppression → allogenic HSCT definitive.

Defects of IL-2 pathway

  • IL-2 mediated signaling is important to maintain immune homeostasis and support the function of Treg lymphocytes

  • CD25 (IL2RA) deficiency – cause immunedeficiency with IPEX-like immune dysregulation, CMV, IL-10↓.

  • Marked by severe diarrhea, failure to thrive, CMV infection, chronic lung disease, lymphadenopathy, splenomegaly, and autoimmunity

  • FOXP3+ cells was preserved in CD25 deficiency; secretion of IL-10, a cytokine with immunosuppressive activity was impaired

  • STAT5B deficiency – AR; also activated in response to growth hormone receptor stimulation—> growth failure with growth hormone insensitivity + autoimmunity.

Autoimmune Lymphoproliferative Syndrome (FAS pathway)

  • Apoptosis of self-reactive lymphocytes important to prevent autoimmunity; induced through the extrinsic Fas-dependent pathway or induction of mitochondrial pathway

  • AD; mutation in FAS gene

  • Lymphadenopathy, splenomegaly, autoimmune cytopenias, and increased risk in developing lymphoma

  • Organ specific complications: glomerulonephritis, hepatitis, encephalitis, uveitis, interstitial pulmonary diseaae

  • Characteristic expanision of CD3+TCRαβ+CD4-CD8- Tcell ( \uparrow double-negative^-), IL-10, sFasL.

  • Mutations: FAS (dominant or somatic), FASL, CASP8/10, KRAS/NRAS (gain).

  • Elevated serum levels of vitamin B12, soluble FasL, IL-10 and IL-18, hypergammaglobulinemia, reduced CD27+ B lymphocytes

  • Rx: Immunosuppressive drugs: Steroids/MMF; HSCT for refractory.

  • Regular monitoring of lymphoproliferation and lymphoma

ITCH E3-ligase deficiency – multisystem autoimmunity, failure to thrive, hepatosplenomegaly

  • failure to thrive, hepatosplenomegaly, multiorgan autoimmune manifestations, chronic lung disease, developmental delay, dysmorphic features and hypotonia

  • Idiscriminate T cell activation, loss of tolerance to self antigens and accumulation of autoreactive B lymphocytes

Cell-Mediated Cytotoxicity Defects

Familial Hemophagocytic Lymphohistiocytosis (FHL)

  • impaired cell-mediated cytotoxicity; inability to clear viral infections causing persistent activation of CD8+ and NK lymphocytes with production of high amounts of IFNα and β and proinflammatory cytokines (TNFα, IL-6)

  • Clinical features: recurrent episodes of high fever, pancytopenia, liver and spleen enlargement and signs of neurologic involvement

  • Criteria: elevated serum levels of triglycerides, ferritin, and soluble CD25, decreased levels of fibrinogen and poor NK function

  • Sever bacterial and fungal infections and multiple organ failure - main causes of death

  • Tx: Corticosteroidsm cyclosporine A, etoposide and ATG; HSCT - only curative treatment

  • AR inheritance

  • Cytolytic granule pathway defects:

    • PRF1 (perforin) deficiency - 30% of all FHL

    • UNC13D (Munc13-4) - impaired priming of cytolytic granules; most common form of FHL

    • STX11 (syntaxin-11) - affect granule exocytosis

    • STXBP2 (Munc18-2)

  • HLH criteria \uparrow ferritin, triglyceride, sCD25, \downarrow fibrinogen; Rx: HLH-2004 chemo → HSCT (RIC).

EBV-Driven Lymphoproliferative IDs (AR trait)

  • XLP1 (SH2D1A/SAP) – express high levels of CD48/CD244; HLH, fatal infectious mononucleosis, aplastic anemia, pulmonary lymphoid granulomatosis with vasculitis, and lymphoma, dysgammaglobulinemia, absent NKT.

    • Tx: HSCT but poorer outcome if HLH is present

  • XLP2 (BIRC4/XIAP) – recurrent HLH with or without EBV infection, inflammatory colitis;

    • Avoid myeloablation in HSCT - definitive treatment

  • ITK deficiency – Hodgkin, EBV pneumonitis, hypogammaglobulinemia, autoimmunity, HLH

  • CD27 deficiency – severe EBV, lymphoma; HSCT curative.

  • CD16 Leu66His homozygous – defective ADCC, herpesvirus infections.

Pathogen-Specific Predispositions

  • Mendelian susceptibility to mycobacterial disease (IL12B, IL12RB1, IFNGR1/2, STAT1) – BCG/NTM/Salmonella; IFN-γ therapy in partial receptor defects.

  • Epidermodysplasia Verruciformis (TMC6/8) – β-HPV skin CA.

  • HSV-1 encephalitis – TLR3, UNC93B1, TICAM1, TRAF3, TBK1 mutations.

  • Trypanosomiasis – APOL1 variants ↑ susceptibility; kidney disease risk in African ancestry.

Humoral Immunodeficiencies

Agammaglobulinemias

  • X-linked (Bruton) agammaglobulinemia; BTK gene expressed in B cells at all stages of development

  • B cell development is impeded at an early stage (pro-B cell to pre-B cell transition

  • \approx 85\%; absent B (CD19^-) & all Ig; sinopulmonary ± enteroviral meningoencephalitis.

  • Asymptomatic during the 1st few months protected by transplacentally acquired maternal antibodies; antibodies fall to low levels by 6 to 9 months — recurrent bacterial infections

  • PE: striking absence of tonsils and palpable lymphoid tissue

  • Serum Ig is absent or extremely low, no B cells; cellular immunity is intact

  • Prone to chronic enteroviral meningoencephalitis and vaccine associated paralytic poliomyelitis

  • Atypical XLA - low numbers of B cells, low level antibody production; milder phenotype

  • Autosomal recessive: mutations of IGHM, IGLL1 (λ5) -prevent formation of the pre B-cell Ig required for B cell development, Igα(CD79a) and Igβ are required for signal transduction by way of the pre-B cell and mature B cell Ig receptors

  • Defect in BLNK (B cell linker protein) and p85 (β-regulatory) subunit of PI3 kinase, PIK3R2 gene/ LRRC8, ⇒ arrest pre-B.

Common Variable Immunodeficiency (CVID)

  • Late-onset humoral immunodeficiency; 15\text{–}35 yrs, pan- or selective hypogammaglobulinemia, poor vaccine response.

  • Hypogammaglobulinemia and impaired specific antibody production are universal

  • Deficiency of IgA, IgM are frequently affected

  • Recurrent sinopulmonary bacterial infections, chronic enteroviral infections, including meningoencephalitis and a form of granulocytic/lymphocytic interstitial lung disease linked to HHV-8 infection

  • More diffuse noncaseating granulomatous disease resembling sarcoidosis

  • Lung disease resembling asthma, chronic rhinitis, chronic giardiasis, and recurrent or chronic arthropathy; atopic symptoms occur in the absence of allergen specific IgE

  • Splenomegaly, adenopathy, and interstitial lymphonodular hyperplasia; high incidence of GI and lymphoid malignancies

  • Cellular immune function is grossly preserved

  • B-memory phenotyping:

    • Switched memory (IgM^-IgD^-CD27^+) ↓ correlates with severity.

    • CD21^{low} expansion correlates with granulomas.

  • Monogenic subsets:

    • ICOS, CD19, CD21, CD81, BAFFR (TNFRSF13C), LRBA, TACI (TNFRSF13B) polymorphisms.

  • Management: IVIG 400\text{–}600 mg kg^{-1} q3–4 w or SCIG 100\text{–}150 mg kg^{-1} weekly + prophylactic antibiotics.

Good Syndrome

  • occurrence of thymoma, immunologic picture similar to CVID with low numbers of B cells and generally more severely impaired T cell function

  • Bacterial sinopulmonary infections and pathogens; more frequently with opportunistic infections, including mucocutaneous candidiasis, severe varicella-zoster virus infection, P.jiroveci, CMV, and recurrent HSV

  • Autoimmune disease is a frequent complication most notably pure red cell aplasia and neutropenia

  • Panhypogammaglobulinemia is a consistent finding

  • Dx: immunophenotypic analysis of peripheral blood lymphocytes frequently show absent or very low numbers of B cells, reduced CD4+ T cells, absent cutaneous delayed hypersensitivity responses and reduced in vitro T cell response to mitogen

Selective IgA Deficiency (SIGAD)

  • IgA1 predominates in serum, IgA1=IgA2 in secretions;

  • Serum IgA <0.07 g/L with normal serum IgG and IgM in a child >4 yrs old; most asymptomatic; ↑ infections, atopy, auto-immunity; some progress → CVID.

  • May occur as drug side effect: phenytoin, carbamazepine, valproic acid, zonisamide, sulfasalazine, gold, penicillamine, hydroxychloroquine and NSAID - IgA may normalize after cessation of drug

IgG Subclass Deficiency / Specific Antibody Deficiency

  • Isolated low IgG2 ± IgG4 commonest; impaired response to polysaccharide vaccines; treat with prophylactic antibiotics ± IVIG if severe.

Hyper-IgM (class-switch) Syndromes

  • CD40L (X-linked), CD40 (AR) – opportunists (P. jiroveci, Cryptosporidium), neutropenia; treat IVIG + HSCT.

  • AID (AICDA) & UNG – B-cell intrinsic; infections mainly bacterial; T cells normal.

Transient Hypogammaglobulinemia of Infancy (THI)

  • IgG >2\sigma below mean but normalizes by 4–5 yrs; manage with prophylactic antibiotics; IVIG rarely.

  • Peripheral lymphoid tissue is sparsely populated with small or no germinal center and markedly reduced plasma cell contents

  • Circulating B and T cells are generally normal

X-linked Immunodeficiency with normal or elevated IgM

  • Genetic lesion is in TNFFSF5 also known as CD40 ligand (CD40L) or CD154

  • selective hypogammaglobulinemia G and A together with normal or elevated amounts of IgM; 1st 2 years of life

  • Recurrent sinopulmonary bacterial infections with opportunistic infections by P.jiroveci, Cryptosporidium, and Histoplasma

  • Prone to development of neutropenia, anemia 2 to parvovirus, stomatitis, sclerosing cholangitis and liver and hematologic malignancies

  • Autoimmune manifestations: cytopenias, arthropathy, and inflammatory bowel disease

  • No B cell memory, vaccination may elicit specific IgM response

  • Secondary lymphoid tissues are sparsely populated and do not contain germinal centers

Management of Humoral Immunodeficiency

  • Antibody titers to specific antigens may be measured before or after immunization

  • Specific antigens most commonly assayed for protein antigens: tetanus and diphtheria toxoid

  • Polysaccharide antigens, measurement of antibodies to pneumococcal serotypes are frequently undertaken

  • Adequacy of carbohydrate responses may be tested by challenge with 24-valent pneumococcal polysaccharide vaccines

  • Unconjugated meningococcal vaccine may be used to assess ability to respond to polysaccharides

  • Isohemagglutinins may be measured as an indicator of the ability to generate polysaccharide antibody

  • High index of suspicion for antibody deficiency should be maintained in patients with recurrent, refractory, or severe infections

IgG Replacement Therapy

  • mainstay of therapy for significantly impaired ability to produce antibody is IgG replacement

  • Given via IV route every 3-4 weeks; IgG can also be administered by subcutaneous infusion

Antibiotic Prophylaxis

  • more common 1st line approach for infection prophylaxis - in milder forms of antibody deficiency

  • Commonly used agents: Amoxicillin, trimethoprim-sulfamethoxazole; clarithromycin or azithromycin, coamox, or doxycycline

  • Therapeutic dose or half dose may be applied

  • IgG therapy may be prescribed if response to antibiotic prophylaxis is poor

General Care

  • regular monitoring for occurrence or progression of complications and adequacy of therapy

  • Periodic measurement of lung function, hematologic parameters, kidney and liver function, and Ig levels

Complement Deficiencies

  • Complement activation:

    • Classical pathway - soluble or surface-bound antigen-antibody complexes

    • Alternative pathway - activated when complexes of C3b, factor B, and properdin are deposited on bacterial surfaces or extracellular matrix components

    • Lectin pathway - initiated by binding of MBL to mannose-containing microbial polysaccharides

  • Common outcome: cleavage (activation) of the C3 complement component to yield C3a (anaphylatoxin) and the C3b fragment - attaches to cell membranes; principal opsonin for phagocytosis

  • Cleavage of C5 component - C5a (anaphylatoxin) and nonenzymatic aggregation of C5b, C6, C7, C8 and C9 to form the macromolecular membrane attack complex (MAC)

Deficiency of Classical Complement Pathway Components

  • C1 deficiency - autoimmune mediated depletion of C1q associated with a resembling SLE and susceptibility to recurrent infections; C1QA, C1QB, C1QC genes closely linked on chromosome 1

  • Screening: CH50 (classical), AH50 (alternative).

  • C3 deficiency ⇒ recurrent pyogenic infections + skin, kidney and joint inflammation caused by immune complex deposition and variety of autoimmune diseases.

Deficiency of Alternative Complement Pathway Components

  • Properdin (X-linked) & factor D ⇒ Neisseria; Factor H / I ⇒ consumption of C3, aHUS, GN.

Deficiency of Lectin Complement Pathway Components

  • Mannose-Binding Lectin low (<100 ng/mL) controversial but may worsen neonatal, chemo, liver-Tx infections.

  • Terminal (C5–9) ⇒ >10-fold risk Neisseria meningitidis.

Deficiency of Complement Regulatory Results

C1 Inhibitor Deficiency (Hereditary Angioedema)

  • AD; unpredictable recurrences of acute and profound subepithelial edema

  • Physical trauma may be a precipitating factor

  • Attacks evolve over a period of 12hours and resolve in 24-48 hours

  • C1-INH limits activities of complement proteases C1r and C1s

    • Type I HAE - C1-INH less than 30%

    • Type II HAE - normal levels of a mutated (nonfunctional) protein

    • Type III HAE - mutations in the gene encoding coagulation factor XII

  • Acquired Angioedema (AAE) type I - C1-INH decrease by an unknown mechanism, usually paraneoplastic process associated with lymphoma and lymphoproliferative orders

  • AAE type II - autoantibodies againsgt C1-INH deplete it from serum

  • Tx: Acute attacks: epinephrine, antihistamine, and corticosteroids are useless; analgesia is indicated for abdominal crises, airway protection is vital

    • Human plasma-derived purified C1 inhibitor Berrinert, a recombinant kallikrein inhibitor, peptidomimetic bradykinin receptor 2 inhibitor

    • FFP - attempts to replace C1-INH ; not first line

    • Tranexamic acid may also be effective

  • Short term prophylaxis is indicated if patient will undergo a procedure that has potential to precipitate an attack

  • Long term prophylaxis - impeded androgens: danazol, stanozolol and oxandrolone - increase expression of normal SERPING1 gene

  • Regulatory: C1-INH absence ⇒ hereditary angio-edema (HAE type I, II); Rx acute (plasma C1-INH 20 U kg^{-1}, ecallantide, icatibant), prophylaxis (danazol, tranexamic acid, SC C1-INH).

Management Principles for Complement Disorders

  • CH50 assay - measures activation of the classical pathway (total classical pathway hemolytic assay)

  • AH50 assay - assess alternative pathway

  • Antibiotic prophylaxis - mainstay of longterm treatment of the infectious predisposition in complement deficiency

  • Eculizumab - anti-C5 monoclonal antibody that inhibits terminal pathway and approved for management of atypical HUS

  • Vigilant surveillance for sinopulmonary & GI infections; periodic PFT, CT, IgG troughs.

  • IgG replacement therapy

    • IVIG 400–600 mg kg^{-1} every 3–4 w or SCIG 100–150 mg kg^{-1} weekly.

    • Goal trough >7–10 g/L; adjust to prevent infections.

  • Vaccination: in agammaglobulinemia & CVID avoid live; killed may be immunogenic in milder defects.

  • Antibiotic prophylaxis: amoxicillin 20 mg kg^{-1} day^{-1} or TMP-SMX 2.5 mg kg^{-1}$$ TMP component.

Key Internet Resources (Table 24-1)

  • ImmunoDeficiency Resource – University of Tampere

  • AAAAI.org – professional society

  • ESID.org – European registry & guidelines

  • USIDNET.org – North American patient registry

  • JMFworld.org / Info4pi.org – Jeffrey Modell Foundation

  • IPOPI.org – international patient advocacy

Figures & Tables (verbal highlights)

  • Fig 24-1: Lymphocyte ontogeny: pluripotent stem → common lymphoid → T (αβ, γδ), B (transitional → mature → memory/plasma), NK.

  • Fig 24-2: Purine salvage; ADA & PNP block → toxic dATP/dGTP accumulation.

  • Fig 24-3: V(D)J recombination machinery & NHEJ (RAG1/2, Artemis, Lig4, Cernunnos, DNA-PKcs).

  • Fig 24-4: γc cytokine receptor family & JAK3-STAT pathways.

  • Fig 24-5: TCR/CD3 complex, ITAMs, Lck/Fyn/ZAP-70 signalling.

  • Fig 24-6: MHC class I assembly (TAP1/2, tapasin).

  • Fig 24-7: Pre-BCR signalling – defects cause agammaglobulinemia.

  • Fig 24-8: Ig heavy-chain constant region gene deletions (six haplotypes).

  • Fig 24-9: T-B collaboration (CD40L/CD40, B7/CD28, IL-4) for class switch.

  • Fig 24-10: Complement pathways (classical, lectin, alternative) converging on C3/C5 convertases & MAC.