Immunodeficiencies

• Overview of congenital B-cell immunodeficiencies

  • X-linked (Bruton) agammaglobulinemia
  • Selective IgA deficiency
  • Common variable immunodeficiency
• X-linked (Bruton) agammaglobulinemia

  • X-linked recessive inheritance
  • BTK gene defect → defective Bruton tyrosine kinase expressed in B cells → complete deficiency of mature B cells
  • Onset: between 3 and 6 months of age when maternal IgG levels in fetal serum start to decrease
  • Recurrent, severe pyogenic infections, especially by encapsulated bacteria and enteroviruses
  • Hypoplasia of lymphoid tissue (e.g., tonsils, lymph nodes)
• Selective IgA deficiency

  • Most common primary immunodeficiency
  • Often asymptomatic
  • May manifest with respiratory infections, and/or chronic diarrhea (e.g., giardiasis)
  • Increased risk of autoimmune diseases like: Gluten-sensitive enteropathy, Inflammatory bowel disease
  • Anaphylactic reaction to products containing IgA
• Common variable immunodeficiency

  • B cells can't differentiate into plasma cells → low Ig's of all classes
  • Clinical symptoms usually develop between 20-40 years of age, but may also manifest during childhood
  • Recurrent sinopulmonary infections
  • Increased risk of lymphoma, autoimmune disorders, and bronchiectasis
• Overview of congenital T-cell immunodeficiencies

  • DiGeorge syndrome
  • Autosomal dominant hyper-IgE syndrome (Job syndrome)
  • IL-12 receptor deficiency
  • Chronic mucocutaneous candidiasis
  • IPEX syndrome
• DiGeorge syndrome

  • Microdeletion at 22q11.2
  • Autosomal dominant inheritance
  • Defective development of 3rd and 4th pharyngeal pouches
  • Hypoplastic or absent thymus and parathyroids
  • Remember the acronym CATCH-22: Cardiac anomalies, Anomalous face, Thymus aplasia/hypoplasia, Cleft palate, Hypocalcemia, Affected chromosome 22
• Autosomal dominant hyper-IgE syndrome (Job syndrome)

  • STAT3 gene mutation → ↓ Th17 cells
  • Defective neutrophil chemotaxis
  • Remember the acronym FATED: Fractures and Facies (coarse facial features), Abscesses (mainly staphylococcal), Teeth (retained primary teeth), Hyper-IgE and Eosinophilia, Dermatologic features (severe eczema)
• IL-12 receptor deficiency

  • Decreased IL-12 → impaired Th1 response → no release of IFN-γ
  • Onset varies but usually 1–3 years of age
  • Disseminated disease, especially tuberculosis
  • Fungal infections
• Chronic mucocutaneous candidiasis

  • Several congenital defects (e.g., STAT1 gain of function mutation, AIRE protein deficiency) → impaired T-cell function → impaired or absent immune response to Candida
  • Noninvasive Candida infections of the skin, nails, and mucous membranes
  • Associated with autoimmune disorders
• IPEX syndrome

  • FOXP3 gene mutation → impaired regulatory T cells → autoimmunity
  • X-linked recessive inheritance
  • Onset: early infancy
  • Lymphadenopathy, chronic lymphoid tissue hypertrophy
  • Autoimmune skin and endocrine disorders (e.g., type 1 DM especially in boys)
  • Enteropathy
  • Failure to thrive
  • Nail dystrophy
• Overview of congenital combined immunodeficiencies

  • Severe combined immunodeficiency
  • Wiskott-Aldrich syndrome
  • Hyper-IgM syndrome
  • Ataxia telangiectasia
• Severe combined immunodeficiency

  • Impaired B cells and T cells
  • X-linked recessive inheritance: defective IL-2R gamma chain
  • Autosomal recessive inheritance: adenosine deaminase deficiency
  • Human RAG mutations: defective VDJ recombination
  • Asymptomatic at birth
  • Recurrent bacterial, viral, and protozoal infections
  • Chronic diarrhea
  • Failure to thrive
  • Lymph nodes and tonsils are hypoplastic
• Wiskott-Aldrich syndrome (WAS)

  • X-linked recessive inheritance
  • WAS gene mutation→ ↓ WAS protein synthesis → impaired remodeling of T-cells actin cytoskeleton → defective antigen presentation
  • Present at birth
  • Remember the acronym WATER: Wiskott-Aldrich, Thrombocytopenia, Eczema, Recurrent infections (especially by encapsulated bacteria)
  • Increased risk of autoimmune disorders and hematological malignancies
• Hyper-IgM syndrome

  • X-linked recessive inheritance
  • Class-switching defect of Th cells (most commonly CD40 ligand deficiency)
  • Recurrent sinopulmonary infections
  • Commonly infected by Pneumocystis jirovecii, Histoplasma, and CMV
  • Failure to thrive
• Ataxia telangiectasia

  • ATM gene defect → failure to recognize and repair dsDNA breaks → no cell cycle arrest → continuous replication of damaged DNA
  • Onset: early childhood
  • Classic triad of 3 As: Progressive ataxia to cerebellar degeneration, Spider telangiectasia, IgA deficiency
  • Susceptibility to infections (e.g., ear infections)
  • Increased risk of malignancies like leukemia and Hodgkin lymphoma
  • Increased sensitivity to ionizing radiation
• Overview of congenital neutrophil and phagocyte disorders

  • Chronic granulomatous disease
  • Leukocyte adhesion deficiency type 1
  • Chédiak-Higashi syndrome
  • Myeloperoxidase deficiency
  • Severe congenital neutropenia
• Chronic granulomatous disease (CGD)

  • X-linked (most common) or autosomal recessive inheritance
  • Defective phagocytic NADPH oxidase
  • Defective ROS production by neutrophils and macrophages
  • Decreased respiratory burst in neutrophils
• Leukocyte adhesion deficiency type 1

  • Absent LFA-1 (CD18) protein → impaired leukocyte chemotaxis and migration
• Chédiak-Higashi syndrome

  • LYST gene defect → defective neutrophil chemotaxis and microtubule polymerization dysfunction → defective lysosome fusion
• Myeloperoxidase deficiency

  • Mutation in MPO gene → partial or complete deficiency of MPO in phagocytes
• Severe congenital neutropenia

  • Variable inheritance
  • Bone marrow failure of myeloid lineage
• Overview of complement disorders

  • C1 esterase inhibitor deficiency
  • Early complement deficiencies (C1, C2, and C4 deficiency)
  • C3 deficiency
  • Terminal complement deficiency
• C1 esterase inhibitor deficiency

  • Autosomal dominant inheritance
  • Unregulated activation of kallikrein → ↑ bradykinin → angioedema
  • Recurrent angioedema triggered by infections, and stress
  • Airway edemas can be life-threatening
• Early complement deficiencies (C1, C2, and C4 deficiency)

  • Mostly autosomal recessive inheritance
  • Most common deficiency: C2
  • ↑ Risk of recurrent infections of the respiratory and sinus
  • ↑ Risk of developing autoimmune diseases
• C3 deficiency

  • Deficiency of C3 and its cleaved fragments (e.g., C3b)
  • Impaired opsonization of pathogens → reduced clearance of C3b-bound immune complexes → ↑ susceptibility to type III HSR
  • Recurrent, severe infections with encapsulated bacteria (e.g., Neisseria meningitidis, Haemophilus influenzae, Streptococcus pneumoniae)
  • Associated with autoimmune diseases (e.g., SLE)
• Terminal complement deficiency

  • Autosomal recessive inheritance
  • Most common deficiencies: C5, C6, and C8
  • Inability to form membrane attack complex
  • Recurrent Neisseria meningococcal and gonococcal pyogenic infections
  • Life-threatening sepsis
  • Associated with SLE and glomerulonephritis
• Primary Immunodeficiencies

  Defect within the immune system - most caused by single gene defect
• Secondary Immunodeficiencies

  Many causes: viruses, medications (immunosuppressants, chemotherapy), malignancies
• History Suggestive of Immunodeficiency

  • Recurrent common bacterial or viral infections
  • Recurrent common infections that require multiple rounds of antibiotics
  • Infections with encapsulated, life-threating, or opportunistic organisms
  • Autoimmune disease, Lymphadenopathy, malignancy, intractable diarrhea, early IBD
  • Family history of Immunodeficiency
  • Recurrent common infections with invasive characteristics
• Laboratory Data

  • CBC with differential - looking for anemia, neutropenia, lymphopenia, eosinophils
  • Serum immunoglobulin levels - vary with age
  • Specific antibody titers to childhood vaccines - ability of the immune system to make Ab and memory B-cells
  • Delayed-type hypersensitivity skin tests to tetanus, candida, mumps - shows presence of Ag-specific T-cells and functioning antigen-presenting cells
• Types of Infection can give you a clue

  • Immunoglobulin defects - bacterial infections
  • T-cell defects - repeat viral, opportunistic, fungal
  • Phagocytic defects - catalase + bacteria (Staph)
  • Complement - encapsulated (Strep, Neisseria)
• Age at Presentation can also give you a clue

  • Severe combined immunodeficiency (SCID) and other combined immunodeficiencies - 1st year of life
  • Antibody deficiencies - after 6 months of age or after many years of life
  • Common variable immunodeficiency (CVID) - young adulthood
  • Congenital neutropenia and phagocyte defects - 1st several months of life
• Other clues can come from the type and location of infection

  • T-cell, or combined immunodeficiency - Opportunistic or severe viral infections
  • B-cell (humoral) defect - Recurrent sinopulmonary infections
  • Neutrophil/phagocyte defect - gingivitis, poor wound healing, omphalitis, granulomas, abscesses without pus
  • Complement defect - Neisseria or early-onset autoimmune disease
• Treatment Principles

  • B-cell (humoral) defects - immunoglobulins
  • Complement defects - frequent vaccines, antibiotic prophylaxis
  • Neutrophil/phagocytic defects - granulocyte colony-stimulating factor (G-CSF) or stem cell transplant
• Severe Combined Immunodeficiency (SCID)

  Both cellular and humoral immune dysfunction, severe lack or dysfunction of T-cells, and primary or secondary B-cell dysfunction
• Genetics of SCID

  • X-linked recessive (most common), autosomal recessive type also
• Possible defects in SCID

  • Defects in common γ chain of IL-2 receptor (MOST COMMON - x-linked recessive)
  • Adenosine deaminase deficiency (autosomal recessive)
  • RAG mutation - VDJ recombination defect
• SCID

  • Small thymus (no thymic shadow on CXR), No lymphocytes in thymus or lymph tissue, Very underdeveloped lymph nodes, adenoids, tonsils
• Presentation of SCID

  • Chronic diarrhea, failure to thrive, thrush, chronic sinopulmonary infections, sepsis, skin infection, opportunistic infections (PCP and CMV pneumonia)
• Do NOT give live vaccines (MMR, varicella) or non-irradiated blood to SCID patients - risk of graft-vs-host disease (GVHD)