Immune Deficiency Syndromes PDF

Immune Deficiency Syndromes Jason Ryan, MD, MPH Immune Deficiency General Principles Loss of T-cells, B-cells, Granulocytes, Complement Acquired: HIV, Chemotherapy Genetic/Congenital: Usually presents in infancy with recurrent infections X-linked Agammaglobulinemia Bruton’s Agammaglobu...

Immune Deficiency Syndromes Jason Ryan, MD, MPH Immune Deficiency General Principles Loss of T-cells, B-cells, Granulocytes, Complement Acquired: HIV, Chemotherapy Genetic/Congenital: Usually presents in infancy with recurrent infections X-linked Agammaglobulinemia Bruton’s Agammaglobulinemia X-linked Failure of B cell precursors to become B cells Light chains not produced Defect in Bruton tyrosine kinase (BTK) gene Symptoms begin ~6 months of age Loss of maternal antibodies X-linked Agammaglobulinemia Bruton’s Agammaglobulinemia Recurrent respiratory bacterial infections Loss of opsonization by antibodies H. Flu, Strep pneumo are common Classic presentation: Recurrent otitis media +/- sinusitis/PNA GI pathogen infections (loss of IgA) Enteroviruses (echo, polio, coxsackie) Giardia (GI parasite) X-linked Agammaglobulinemia Bruton’s Agammaglobulinemia Key findings: Mature B cells (CD19, CD20, BCR) absent in peripheral blood Underdeveloped germinal centers of lymph nodes Absence of antibodies (all classes) Treatment: IVIG Selective IgA Deficiency Very common syndrome in US (~1 in 600) Defective IgA B-cells (exact mechanism unknown) Most patients asymptomatic Symptomatic patients: Recurrent sinus, pulmonary infections Otitis media, sinusitis, pneumonia Recurrent diarrheal illnesses from Giardiasis Blood transfusions → anaphylaxis IgA in blood products Antibodies against IgA in IgA deficient patients SLE and RA are common (20-30%) Selective IgA Deficiency Diagnosis: Serum IgA < 7mg/dl Normal IgG, IgM Treatment: Prophylactic antibiotics IVIG Special features: False positive β-HCG test Heterophile antibodies produced in IgA deficiency Lead to false positive β-HCG Up to 30% IgA deficient patients test positive for β-HCG CVID Common Variable Immunodeficiency Defective B cell maturation Loss of plasma cells and antibodies Many underlying genetic causes Most cases due to unknown cause 10+ genes mutations associated with CVID Often sporadic – no family history Normal B cell count, absence of antibodies Usually IgG Sometimes IgA and IgM (variable) CVID Common Variable Immunodeficiency Similar to X-linked Agammaglobulinemia Recurrent respiratory bacterial infections Enteroviruses, Giardiasis Key differences: Not X-linked (affects females) Later onset (majority 20-45 years old) ↑ frequency other diseases: RA, pernicious anemia, lymphoma B Cell Disorders IgA Def Bruton’s CVID B Cells Normal ↓ Normal Antibodies ↓ IgA ↓ IgA, IgM, IgG ↓ IgA, IgM, IgG Symptoms Sinopulmonary Sinopulmonary Sinopulmonary GI GI GI Special False + β-HCG Infancy 20s-40s Features SLE/RA Autoimmune Lymphoma Thymic Aplasia DiGeorge Syndrome Failure of 3rd/4th pharyngeal pouch to form 24-28 Day Old Embryo Wikipedia/Public Domain Thymic Aplasia DiGeorge Syndrome Most cases: 22q11 chromosomal deletion Key point: Not familial Classic triad: Loss of thymus (Loss of T-cells, recurrent infections) Loss of parathyroid glands (hypocalcemia, tetany) Congenital heart defects (“conotruncal”) Heart Defects: Abnormal aortic arch Truncus arteriosus Tetralogy of Fallot ASDs/VSDs Thymic Aplasia DiGeorge Syndrome Immune symptoms Recurrent infections Viral, fungal, protozoal, intracellular bacteria Immune symptoms sometimes improve Cleft palate, mandible problems also common Thymic Aplasia Key Findings No thymus shadow on CXR Thymus large in newborns Faint white shadow on chest x-ray Also seen in SCID (without ↓Ca, facial/heart abnormalities) Low T-cell count Underdeveloped T-cell structures Paracortex in lymph nodes Peri-arteriolar sheaths in spleen Treatment: Thymic transplantation Hematopoietic cell transplantation Hyper-IgE Syndrome Job’s Syndrome Rare syndrome, poorly understood Immune symptoms with skin/bone findings Defective CD4+ Th17 cells Failure to produce IL-17 Loss of attraction of neutrophils Defects of STAT3 signaling pathway Signal transducer and activator of transcription Activated by cytokines Overproduction IgE, loss of IFN-γ Characteristic labs: ↑IgE, ↓IFN-γ Hyper-IgE Syndrome Job’s Syndrome Skin findings First few weeks of life Diffuse eczema (also crusted lesions, boils, etc.) Histamine release → itching Staph abscesses face, scalp Classically “cold” - lacking warmth/redness of inflammation Loss of cytokine production Recurrent sinusitis, otitis (often without fever) Facial deformities (broad nasal bridge) Retained primary teeth (two rows of teeth!) Wikipedia/Public Domain Hyper-IgE Syndrome Job’s Syndrome Classic case: Newborn baby Deformed face/teeth Diffuse rash Skin abscesses that are “cold” Recurrent infections without fever Labs: Elevated IgE Chronic mucocutaneous candidiasis Defect in autoimmune regulator (AIRE) genes AIRE Function #1: Associates with Dectin-1 receptor Dectin-1 responds to Candida antigens Result of defect: Recurrent candida infections AIRE Function #2: Promotes self antigens production in thymus Self antigens presented to T-cells (negative selection) Result of defect: Autoimmune T-cells Endocrine dysfunction (parathyroid/adrenal) Chronic mucocutaneous candidiasis T-cell dysfunction (cell-mediated defect) Th1 cytokines: ↓IL-2, ↓IFN-γ ↑IL-10 (anti-inflammatory cytokine) NOT due to antibody or B-cell deficiencies T cells fail to react to candida antigens D Lilic. New perspectives on the immunology of chronic mucocutaneous candidiasis. Curr Opin Infect Dis. 2002; 15(2):143-7 Chronic mucocutaneous candidiasis Chronic skin, mucous membrane candida infections Thrush Skin Esophagus Associated with endocrine dysfunction: Hypoparathyroidism Adrenal failure Classic case: Child with recurrent thrush, diaper rash Candida Infections T-cells important for mucosal defense Example: HIV patients often get thrush (↓CD4) Neutrophils important for systemic defense HIV patients rarely get candidemia No candidemia in CMC Chemo patients at risk for candidemia (neutropenia) SCID Severe Combined Immunodeficiency Loss of cell-mediated and humoral immunity Usually primary T cell problem Loss of B-cells, antibodies usually secondary SCID Severe Combined Immunodeficiency T-cell/B cell areas absent/diminished: Loss of thymic shadow Loss of germinal centers in nodes Susceptible to many infections Thrush, bacterial, viral, fungal Babies: Thrush, diaper rash, failure to thrive Death unless bone marrow transplant SCID Severe Combined Immunodeficiency Most common forms are X-linked (boys) Mutation of γ subunit of cytokine receptors Gene: IL2RG (interleukin-2 receptor gamma gene) Also caused by adenosine deaminase gene deficiency Newborn screening: Maternal T-cells may falsely indicate normal counts TRECs (T-cell receptor excision circles) Circular DNA formed in normal T-cells in the thymus Mandated in many states SCID Severe Combined Immunodeficiency Classic case: Infant with recurrent infections Multiple systems: otitis, GI, candida (skin) Absent thymic shadow Normal calcium/heart (contrast with DiGeorge) ADA Adenosine Deaminase Deficiency Excess dATP Believed to inhibit ribonucleotide reductase Ribonucleotides synthesized first (A, G, C, U) Converted to deoxyribonucleotides by RR Result: ↓ DNA synthesis → B/T cell dysfunction ADA Adenosine Inosine dATP Ataxia Telangiectasia Autosomal recessive genetic disorder Defective ATM gene on chromosome 11 Ataxia Telangiectasia Mutated gene Repairs double stranded DNA breaks Nonhomologous end-joining (NHEJ) Result: Failure to repair DNA mutations Hypersensitivity of DNA to ionizing radiation Nonhomologous end-joining NHEJ Double Strand Break NHEJ (ionizing radiation) Ataxia Telangiectasia Mix of systems involved with varying findings CNS (ataxia) Skin (telangiectasias) Immune system (infections, malignancies) Presents in childhood with progressive symptoms Usually begins with gait and balance problems Ataxia Telangiectasia Cerebellar atrophy Ataxia in 1st year of life Telangiectasias Dilation of capillary vessels on skin Repeated sinus/respiratory infections Low levels immunoglobulins, especially IgA and IgG High risk of cancer (lymphomas) Commonly identified lab abnormalities: Most consistent lab finding: ↑AFP Low IgA level Hyper-IgM Syndrome Class switching disorder Failure of B cells (CD40) to T cell (CD40L) binding 70% cases: Defective CD40L gene (T-cell problem) B cells make IgM only Labs show ↑IgM, all other antibodies absent Most common form X-linked (boys) T Cell Dependent Activation CD40L CD40 TCR T Cell CD4 MHC2 B Cell B7 CD28 Hyper-IgM Syndrome Recurrent bacterial infections in infancy Sinus and pulmonary infections Pneumonia, sinusitis, otitis media Mostly caused by encapsulated bacteria (S. pneumo, H. flu) Also opportunistic infections Pneumocystis, Cryptosporidium, Histoplasmosis Loss of IgG opsonization Wiskott-Aldrich Syndrome X linked disorder of WAS gene (WAS protein) WASp absence/dysfunction Necessary for T-cell cytoskeleton maintenance This forms “immunologic synapse” T-cells cannot properly react to APCs Can worsen with age Immune dysfunction, ↓platelets, eczema Elevated IgE and IgA common (eczema) Treatment: Bone marrow transplant Wiskott-Aldrich Syndrome Classic case Male infant 6 months old (maternal antibodies fade) Eczema Bleeding, petechiae (low platelets) Recurrent infections Wikipedia/Public Domain Leukocyte Adhesion Deficiency Defective neutrophil/lymphocyte migration Most common type: Type 1 Autosomal recessive defect in CD18 Also called Lymphocyte function associated antigen-1 (LFA1) Forms beta subunit of several integrins (adhesion molecules) WBCs (especially PMNs) cannot roll, migrate Leukocyte Adhesion Deficiency Delayed separation of the umbilical cord After cord cutting, inflammation occurs Cord stump normally falls off 2-3 days Delayed in LAD (sometimes 30+ days) Classic presenting infection: omphalitis (stump infection) Other findings: Recurrent bacterial infections Elevated WBCs (neutrophilia) – especially during infections Chediak-Higashi Syndrome Failure of lysosomes to fuse with phagosomes Mutation: lysosomal trafficking regulator (LYST) gene Causes microtubule dysfunction Recurrent bacterial infections Especially Staph and Strep Oculocutaneous albinism Fair skin, blond hair, light blue eyes Children who survive → severe neuro impairment Peripheral neuropathy: weakness and sensory deficits Often wheelchair bound CGD Chronic Granulomatous Disease Loss of function of NADPH oxidase Phagocytes use NADPH oxidase to generate H2O2 from oxygen (respiratory burst) Catalase (-) bacteria generate their own H2O2 which phagocytes use despite enzyme deficiency Catalase (+) bacteria breakdown H2O2 Host cells have no H2O2 to use → recurrent infections Five organisms cause almost all CGD infections: Staph aureus, Pseudomonas, Serratia, Nocardia, Aspergillus Source: UpToDate CGD Chronic Granulomatous Disease NADPH O2 Oxidase O2· H2O2 Bacteria CGD Chronic Granulomatous Disease NADPH O2 Oxidase O2· H2O2 Bacteria Catalase (-) Bacteria CGD Chronic Granulomatous Disease NADPH O2 Oxidase O2· H2O2 Bacteria Catalase (+) H2O Bacteria O2 CGD Chronic Granulomatous Disease Nitroblue tetrazolium test Dye added to sample of neutrophils Absence of NADPH oxidase → cells do not turn blue A “negative” test indicates lack of enzyme More blue, more NADPH oxidase present Innate Immunity Defects Disorder Features Leukocyte Adhesion Deficiency ↓↓ Neutrophil migration Chediak-Higashi Lysosome fusion; microtubules ↓↓ Respiratory Burst; Chronic Granulomatous Disease Catalase (+) Infections