Immunology

Limited scleroderma (CREST syndrome)

Anti-Jo-1 = anti-histidyl-tRNA synthetase Polymyositis, dermatomyositis

Hashimoto thyroiditis

Primary biliary cirrhosis

Anti-DNA topoisomerase I antibody. Diffuse scleroderma

Autoimmune hepatitis type 1

Sjögren syndrome

Mixed connective tissue dissease

- Microscopic polyangiitis - Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) - Ulcerative colitis

Granulomatosis with polyangiitis (Wegener)

Rheumatoid arthritis

Developmental failure to produce mature B-cells and plasma cells, resulting in agammaglobulinemia.- Defect in BTK, a tyrosine kinase gene → no B-cell maturation - X-linked recessive (↑ in boys) - Recurrent bacterial and enteroviral infections after 6 months (↓ maternal IgG).- Infections include pharyngitis, otitis media, bronchitis, pneumonia; commonly H influenza, S pneumococcus, S aureus. Findings:- Absent B cells and normal T cells in peripheral blood- ↓ Ig of all classes- Absent/scanty lymph nodes and tonsils- Live vaccines contraindicated

- Most common 1° immunodeficiency - Majority asymptomatic- Airway and GI infections (eg, Giardia)- Autoimmune disease (eg, celiac disease, inflammatory bowel disease)- Atopy- Anaphylaxis to IgA-containing products Findings: - ↓ IgA with normal IgG, IgM levels- ↑ susceptibility to giardiasis

Defect in B-cell differentiation. Cause unknown. - Usually presents after age 2 and may be considerably delayed (age 25-35). - Sinupulmonary infections- ↑ risk of autoimmune disease (eg, rheumatoid arthritis, ITP, vitiligo)- Bronchiectasis- ↑ risk of lymphoma Findings:- ↓ plasma cells- ↓ immunoglobulins

22q11 deletion; failure to develop 3rd and 4th pharyngeal pouches → absent thymus and parathyroids - Tetany (hypocalcemia)- Recurrent viral/fungal infections (T-cell deficiency)- Conotruncal abnormalities (eg, tetralogy of Fallot, truncus arteriosus)- Dysmorphic facial features: prominant nasal bridge, dysplasic ears, micrognathia, cleft palate Findings:- ↓ T cells, ↓ PTH, ↓ Ca2+- Delayed hypersensitivity skin testing- Absent thymic shadow on CXR- 22q11 deletion detected by FISH

Several types including defective IL-2R gamma chain (most common, X-linked), adenosine deaminase deficiency (autosomal recessive) - Failure to thrive- Chronic bacterial diarrhea- Chronic candidiases (eg, thrush)- Recurrent viral, bacterial, fungal, and protozoal infections Findings:- ↓ T-cell receptor excision circles (TRECs)- Absence of thymic shadow (CXR), germinal centers (lymph node biopsy), and T cells (flow cytometry) Treatment: - Avoid live vaccines- Give antimicrobial prophylaxis and IVIG- Bone marrow transplant curative (no concern for rejection)

Defects in ATM gene → failure to detect DNA damage → failure to halt progression of cell cycle and perform non-homologous end-joining → mutations accumulate - Autosomal recessive Triad:- Cerebellar defects (ataxia)- Spider angiomas (telangiectasia)- IgA deficiency Findings:- ↑ AFP- ↓ IgA, IgG, and IgE- Lymphopenia, cerebellar atrophy- ↑ risk of lymphoma and leukemia

Most commonly due to defective CD40L on Th cells → class switching defect - X-linked recessive - Severe pyogenic infections early in life- Opportunistic infection with Pneumocystis, Cryptosporidium, CMV hepatitis- Cryptosporidium enteritis → biliary disease → cholangiocarcinoma Findings:- normal or ↑ IgM- ↓↓ IgG, IgA, IgE- Failure to make germinal centers Treatment:- IV immunoglobulin therapy- Prophylactic antibiotics- Recombinant human granulocyte-colony stimulating factor administration- Stem cell transplantation may be curative.

Mutation in WASp gene; leukocytes and platelets unable to reorganize actin cytoskeleton → defective antigen presentation - X-linked recessive - Eczema- Thrombocytopenia- Recurrent (pyogenic) infections- ↑ risk of autoimmune disease and hematological malignancies - ↓ to normal IgG, IgM- ↑ IgE, IgA- Thrombocytopenia with small platelets

Defect in LFA-1 integrin (CD18) protein on phagocytes; impaired leukocytic migration and chemotaxis (especially tight binding, adhesion). - Autosomal recessive - Recurrent nonsuppurative bacterial skin and mucosal infections (eg, omphalitis, periodontitis)- Absent pus formation - Impaired wound healing- Delayed (>30 days) separation of umbilical cord - Marked peripheral leukocytosis with ↑ neutrophils in blood- Absence of neutrophils at infection sites.

Defect of NADPH oxidase → ↓ reactive oxygen species (eg, superoxide) and ↓ respiratory burst in neutrophils. - X-linked form most common - ↑ susceptibility to catalase ⊕ organisms (Nocardia, Pseudomonas, Listeria, Aspergillus, Candida, E coli, Staphylococci, Serratia) Findings:- Abnormal dihydrorhodamine (flow cytometry) test (↓ green fluorescence)- Nitroblue tetrazolium dye reduction test fails to turn blue

Defect in lysosomal trafficking regulator gene (LYST).Microtubule dysfunction in phagosome-lysosome fusion. - Autosomal recessive - Lymphohistiocytosis- Partial albinism- Recurrent pyogenic infections by staphylococci and streptococci- Peripheral neuropathy: tingling and other paresthesias in limbs - Giant granules in granulocytes and platelets- Pancytopenia- Mild coagulation defects

Increases risk of severe, recurrent pyogenic sinus and respiratory tract infections ↑ susceptibility to type III hypersensitivity reactions

Causes hereditary angioedema due to unregulated activation of kallikrein → ↑ bradykinin. Characterized by ↓ C4 levels. ACE inhibitors are contraindicated. - Facial swelling without urticaria- Life-threatening laryngeal edema- Gastrointestinal manifestations (eg, nausea, vomiting, colicky pain, diarrhea)

Deficiency of Th17 cells due to STAT3 mutation → defect in neutrophil chemotaxis - Autosomal dominant FATED:- Coarse facies- Staphylococcal abscesses (noninflamed)- Retained primary teeth- ↑ IgE- Dermatologic problems (severe eczema)- Bone fractures from minor trauma Findings:- ↑ IgE, ↓ IFN-γ- ↑ eosinophils

↓ Th1 response - Autosomal recessive - Disseminated mycobacterial and fungal infections (eg, Salmonella)- May present after administration of BCG vaccine with tuberculosis infection Findings: ↓ IFN-γ

T-cell dysfunction. Can result from congenital genetic defects in IL-17 or IL-17 receptors. - Noninvasive Candida albicans infections of skin and mucous membranes Findings:- Absent in vitro T-cell proliferation in response to Candida antigens- Absent cutaneous reaction to Candida antigens

Interleukin-1: Causes fever, acute inflammation. Activates endothelium to express adhesion molecules. Induces chemokine secretion to recruit WBCs. Also known as osteoclast-activating factor. Interleukin-6: Causes fever and stimulates production of acute-phase proteins. Interleukin-8: Major chemotactic factor for neutrophils. Interleukin-12: Induces differentiation of T cells into Th1 cells. Activates NK cells. Tumor necrosis factor-α: Activates endothelium. Causes WBC recuitment, vascular leak.

Interferon-γ: - Secreted by NK cells and T cells in response to antigen or IL-12 from macrophages. - Stimulates macrophages to kill phagocytosed pathogens.- Inhibits differentiation of Th2 cells. - Also activates NK cells to kill virus-infected cells. - Increases MHC expression and antigen presentation by all cells.

Interleukin-4: Induces differentiation of T cells into Th2 cells. Promotes growth of B cells. Enhances class switching to IgE and IgG. Interleukin-5: Promotes growth and differentiation of B cells. Enhances class switching to IgA. Stimulates growth and differentiation of eosinophils. Interleukin-10: Attenuates inflammatory response. Decreases expression of MHC class II and Th1 cytokines. Inhibits activated macrophages and dendritic cells. Also secreted by regulatory T cells.

MHC encoded by HLA genes. Present antigen fragments to T cells and bind T-cell receptors (TCRs). MHC I:- HLA-A, HLA-B, HLA-C- Binding: TCR and CD8- 1 long chain, 1 short chain, β2-microglobulin- Expression: All nucleated cells, APCs, platelets. Not on RBCs.- Present endogenously synthesized antigens (eg, viral or cytosolic proteins) to CD8+ cells- Antigen peptides loaded onto MHC I in RER after delivery via TAP (transporter associated with antigen processing). MHC II:- HLA-DP, HLA-DQ, HLA-DR- Binding: TCR and CD4- 2 equal-length chains, invariant chain- Expression: APCs- Present exogenously synthesized antigens (eg, bacterial proteins) to CD4+ cells- Antigen loaded following release of invariant chain in an acidified endosome

Hemochromatosis

- Addison disease - Myasthenia gravis - Graves disease

- Anklyosing spondylarthritis - Psoriasis arthritis - Inflammatory bowel diseases-associated arthritis - Reactive arthritis AKA seronegative arthropathies

Celiac disease

- Multiple sclerosis - Hay fever - SLE - Goodpasture syndrome

- Diabetes mellitus type 1 - SLE (2,3, S-L-E) - Graves disease - Hashimoto thyroiditis - Addison disease

- Rheumatoid arthritis - Diabetes mellitus type 1 - Addison disease

Hashimoto thyroiditis

Increased risk of severe, recurrent pyogenic sinus and respiratory tract infections. Increased risk of SLE.

Increased susceptibility to recurrent Neisseria bacteremia.

A defect in the PICA gene preventing the formation of GPI-anchors for complement inhibitors, such as decay-accelerating factor (DAF/CD55) and membrane inhibitor of reactive lysis (MIRL/CD59). Causes complement-mediated lysis of RBCs.

Type I hypersensitivity reaction against plasma proteins in transfused blood. IgA deficient individuals must receive blood products without IgA. Presentation:- Urticaria- Pruritus- Fever- Wheezing- Hypotension- Respiratory arrest- Shock Timing: Within minutes to 2-3 hours

Two known mechanisms:- Type II hypersensitivity reaction with host antibodies against donor HLA and WBCs- Induced by cytokines that are created and accumulate during the storage of blood products Presentation:- Fever- Headaches- Chills- Flushing Timing: Within 1-6 hours

Type II hypersensitivity reaction. Intravascular hemolysis (ABO blood group incompatibility) or extravascular hemolysis (host antibody reaction against foreign antigen on donor RBCs). Presentation:- Fever- Hypotension- Tachypnea- Tachycardia- Flank pain- Hemoglobinuria (intravascular hemolysis)- Jaundice (extravascular hemolysis) Timing: Within 1 hour

Donor anti-leukocyte antibodies against recipient neutrophils and pulmonary endothelial cells. Presentation:- Respiratory distress - Noncardiogenic pulmonary edema Timing: Within 6 hours

Antiphospholipid syndrome

- SLE - Antiphospholipid syndrome

SLE

Drug-induced lupus