Pathoma 2023 PDF_p25-26.pdf

Www.Medicalstudyzone.com Inflammation, Inflammatory Disorders, and Wound Healing 17 B. Increased risk for bacterial, enterovirus, and Giardia lamblia infections, usually in late childhood C. Increased...

Www.Medicalstudyzone.com Inflammation, Inflammatory Disorders, and Wound Healing 17 B. Increased risk for bacterial, enterovirus, and Giardia lamblia infections, usually in late childhood C. Increased risk for autoimmune disease and lymphoma V. IgA DEFICIENCY A. Low serum and mucosal IgA; most common immunoglobulin deficiency B. Increased risk for mucosal infection, especially viral; however, most patients are asymptomatic. VI. HYPER-IgM SYNDROME A. Characterized by elevated IgM B. Due to mutated CD40L (on helper T cells) or CD40 receptor (on B cells) 1. Second signal cannot be delivered to helper T cells during B-cell activation. 2. Consequently, cytokines necessary for immunoglobulin class switching are not produced. C. Low IgA, IgG, and IgE result in recurrent pyogenic infections (due to poor opsonization), especially at mucosal sites. VII. WISKOTT-ALDRICH SYNDROME A. Characterized by thrombocytopenia, eczema, and recurrent infections (defective humoral and cellular immunity); bleeding is a major cause of death B. Due to mutation in the WASP gene; X-linked VIII. COMPLEMENT DEFICIENCIES A. C5-C9 deficiencies-increased risk for Neisseria infection (N gonorrhoeae and N meningitidis) B. Cl inhibitor deficiency-results in hereditary angioedema, which is characterized by edema of the skin (especially periorbital, Fig. 2.3) and mucosal surfaces AUTOIMMUNE DISORDERS I. BASIC PRINCIPLES A. Characterized by immune-mediated damage of self tissues 1. US prevalence is 1%-2%. B. Involves loss of self-tolerance 1. Self-reactive lymphocytes are regularly generated but develop central (thymus and bone marrow) or peripheral tolerance. 2. Central tolerance in thymus leads to T-cell (thymocyte) apoptosis or generation of regulatory T cells. i. AIRE mutations result in autoimmune polyendocrine syndrome. 3. Central tolerance in bone marrow leads to receptor editing or B-cell apoptosis. 4. Peripheral tolerance leads to anergy or apoptosis of T and B cells. i. Fas apoptosis pathway mutations result in autoimmune lymphoproliferative syndrome (ALPS). 5. Regulatory T cells suppress autoimmunity by blocking T-cell activation and producing anti-inflammatory cytokines (IL-10 and TGF-β ). i. CD25 polymorphisms are associated with autoimmunity (MS and type 1DM). ii. FOXP3 mutations lead to IPEX syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked). C. More common in women; classically affects women of childbearing age 1. Estrogen may reduce apoptosis of self-reactive B cells. D. Etiology is likely an environmental trigger in genetically-susceptible individuals. 1. Increased incidence in twins  Www.Medicalstudyzone.com 18 FUNDAMENTALS OF PATHOLOGY 2. Association with certain HLA types (e.g., HLA-B27) and PTPN22 polymorphisms 3. Environmental triggers lead to bystander activation or molecular mimicry. E. Autoimmune disorders are clinically progressive with relapses and remissions and often show overlapping features; partially explained by epitope spreading II. SYSTEMIC LUPUS ERYTHEMATOSUS A. Chronic, systemic autoimmune disease 1. Flares and remissions are common. B. Classically arises in middle-aged females, especially African American and Hispanic women 1. May also arise in children and older adults (less dramatic gender bias) C. Antigen-antibody complexes damage multiple tissues (type III HSR). 1. Poorly-cleared apoptotic debris (e.g., from UV damage) activates self-reactive lymphocytes, which then produce antibodies to host nuclear antigens. 2. Antigen-antibody complexes are generated at low levels and taken up by dendritic cells. 3. DNA antigens activate TLRs, amplifying immune response (IFN-α). 4. Antigen-antibody complexes are subsequently generated at higher levels and deposit in multiple tissues causing disease. 5. Deficiency of early complement proteins (C1q, C4, and C2) is associated with SLE. D. Almost any tissue can be involved. Classic findings include 1. Fever, weight loss, fatigue, lymphadenopathy, and Raynaud phenomenon 2. Malar 'butterfly' rash (Fig. 2.4A) or discoid rash (Fig. 2.4B), especially upon exposure to sunlight 3. Oral or nasopharyngeal ulcers (usually painless) 4. Arthritis (usually involving ≥ 2 joints) 5. Serositis (pleuritis and pericarditis) 6. Psychosis or seizures 7. Renal damage i. Diffuse proliferative glomerulonephritis is the most common and most severe form of injury. ii. Other patterns of injury (e.g., membranous glomerulonephritis) also occur. 8. Anemia, thrombocytopenia, or leukopenia (type II HSR) 9. Libman-Sacks endocarditis 10. Antinuclear antibody (ANA; sensitive, but not specific) 11. Anti-dsDNA or anti-Sm antibodies (highly specific) E. Antiphospholipid antibody is associated with SLE (one-third of patients). 1. Autoantibody directed against proteins bound to phospholipids Fig. 2.4A Malar 'butterfly' rash, SLE. Fig. 2.48 Discoid rash, SLE.