Pathology immunology

A primary immunodeficiency - failure of B cell precursors (pre and pro-B cells) to mature into B cells

Mutations in cytoplasmic tyrosine kinase BTK on X chromosome Xq21 - no light chains products, no Ig receptor can form (no IgM or IgD on surface). X-linked recessive, males

CD19 pos B cells markedly decreased or absent and serum levels of all Igs are depressed, with IgGs much more severely depressed. Plasma cells absent. T cell reactions normal.

Present at 6 months when maternal Abs wane - recurrent bacterial infections of respiratory tract H.flu, S. pneu, etc, Giardia and viruses in bowel.

Primary immunodeficiency affecting childhood and young adults - heterogenous group of disorders, hypo gammglobulinemia affecting all antibody classes. Dx of exclusion.

Normal number of B cells in tissue and blood, just dysfunctional. Underlying mechanisms not entirely understood.

Most common primary immunodeficiency, often asymptomatic- low levels of both secreted and serum IgA.

Infections in the mucosal lined tracts- GI, respiratory, urogenital.

High frequency of concurrent autoimmune disease- SLE and RA

Number of IgA B cells normal, but cannot turn into plasma cells for unknown reason

IgA deficient patients can develop fatal anaphylaxis when transfused with blood product with normal IgA.

Primary immunodeficiency - patients able to make IgM however cannot isotype switch to IgG IgA or IgE.

Underlying defect is in helper T cells CD4+ with a defect in either CD40Ligand in Thelper cells or CD40 on B cells. Cannot stimulate isotype switch. Mutations on X chromosome (70%).

Pts present with recurrent pyogenic infections due to lack of opsonizing ability. Number of B and T cells normal. IgM normal to increased

Thymic hypoplasia as a result of failure of development of third and fourth branchial pounches

Deletion of gene on chromosome 22q11 (90%) - Tbox family, unknown

Loss of T cell immunity, tetany (hypoparathyroid), and congenital facial and heart defects.

Heteregeneous group of disorders with defects in both humoral and cell mediated immune responses

Most common form is X-linked (males) - mutation in common gamma chain subunit of cytokine receptor. Mutated cannot bind IL-7, thus T cell precursors cannot mature.

ADA deficiency is autosomal recessive

Extremely susceptible to wsevere infections by a wide range of pathogens- C alba, PCP, Psuedom, CMV, VZV, etc.Usually SCID defect resides in the T cell compartment with secondary impairment of B cells.

X-linked recessive (male) characterized by thrombocytopenia, eczema, and marked vulnerability to recurrent infection ending in early death.

Maps to Xp11 WASP protein encoded, signal transduction. Etiology is unknown.

HIV-1(everywhere else) and HIV-2 (west africa and india)

p24 is antigen detected on ELISA

HIV infects CD4+ lymphocytes, monocytes and macrophages in blood, lymphoid tissue, and CNS.

gp120 binds CD4 but also requires coreceptors CCR5 or CXCR4 for infection. gp41 involved in membrane penetration.

• Opportunistic infections:
• crypto, pcp. toxo. candida, cocci, histo, atypical MAC, nocardia, salmonella, cmv, hsv,vav, PML

• Neoplasms-
• Kaposi sarcoma, associated with HHV-8 coinfection. ?neoplastic versus proliferative process, more widespread than sporatic forms
• B cell lymphoma - EBV association
• CNS lymphoma - 1000x more common in AIDS patients
• Cervical carcinoma

• Autosomal recessive, mutated ATM gene on chr 11. ATM involved in p53-dependent pathway
• Clinically- cerebellar ataxia, predisposition to hematolymphoid malignancies, x-ray hypersensitivity, ocular and cutaneous telangiectasias.

Autosomal recessive , mutations in MHC class II molecules. Lack HLA-DR, DP, DQ. Early infections. Lack CD4+ T cells.

• Autosomal dominant, mutations in Fas-related proteins leads to lack of Fas pathway. Inability toi rid of autoreactive lymphocytes (problems with apoptosis). Increased CD4-/ CD8- double negative T lymphocytes.
• Children present with lymphoproliferation, hepatomegaly, splenomegaly. Lymph node with marked paracortical expansion. Later in life often develop autoimmune dz.

Genetic deficiency in C1-inhibitor, autosomal dominant, angioedema without urticaria, classic pathway complement activation results in low C2 and C4. C3 is usually normal.

X-linked, deficiency in NADPH oxidase, presents early in life with bacterial (catalas positive, staph) and fungal infections (esp aspergillus). Screening test is nitroblue tetrazolium, gets reduced to blue compound. Diffuse granulomata in respiratory, GI tract, urogenital tract. Association with Kx deficiency (McLeod phenotype) due to gene proximity on X-chromosome.

Autosomal recessive, associated with delayed separation of umbilical cord, recurrent bacterial infections as phagocytes cannot migrate to wound. No pus. Deficiency in CD18 (beta integrin).

Autosomal recessive, deficient sialyl Lewis X (Bombay phenotype), no delayed umbilical cord detachment, better survival than type I

Autosomal recessive, defect in CHS gene involved in cellular organelle trafficking, results in oculutaneous albinism (silver grey hair), giant lysosomes in leukocytes and fibroblasts. Triad of thrombocytopenia, neuropathy, defective platelets (easy bruising). Increased risk for leukemia and lymphoma. Often fatal in childhood.

SLE, MCTD, Scl, Sjogrens

SLE, drug-induced lupus

Scleroderma,

CREST syndrome, Raynauds phenomenon

SLE

Anti-dsDNA test. Pt serum antibodies bind against kinetophore on cirthidia organism and fluoresce for positive assay.

Usually IgM directed against the Fc portion of IgG, not specific for RA.

• Wegener's granulomatosis (90%)
• associated with anti Proteinase 3 antibodies

• Microscopic polyangiitis (50%)
• Churg Strauss (60%)
• associated with anti-MPO antibodies

IBD (ulcerative colitis, crohns) autoimmune hepatitis, etc.

pANCA pattern positive, however antibody not against MPO