Tolerance and Autoimmunity Flashcards
Central Tolerance
Occurs in the generative lymphoid organs
Positive selection produces immature T cells that then move to the medulla. Any cells that recognize high avidity self antigens presented on MHC class II or class I are killed through apoptosis (exception of T-reg cells)
Peripheral Tolerance (Random process)
Apoptosis:
Anergy:
Suppression:
Apoptosis: Fas/Fas ligand binding results in apoptosis/ cytokine withdrawal
Anergy: The functional inactivation of T-lymphocyte - Antigen presenting cells that lack costimulatory molecules such as B7 promote anergy (2nd signal = CD28)
Suppression: Dominant suppression by T-regs
Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED)
Clinical syndrome characterized by autoimmune adrenal and parathyroid diseases (also associated with fungal infections)
APECED
Defect in _____ gene
Failure of _______ tolerance
Deletion of _________ T-cells
Defect in *Aire *gene
Failure of Central tolerance
Deletion of self-reactive T-cells
APECED
Lab findings:
- Low cortisol
- Low calcium, Low PTH
- Hyponatremia, hypocalcemia, hyperkalemia
- Thrush
Autoimmune lymphoproliferative syndrome (ALPS) presents with:
- Lymphadenopathy
- Splenomegaly
- Autoimmune cytopenias
ALPS
Mutations in ______ or _____ _____
High levels of _____
Failure of ______ tolerance
Mutations in fas or fas ligand
High levels of immunoglobulins (IgG, IgA, IgM)
Failure of peripheral tolerance
ALPS
Lab findings:
- Hypergammaglobulinemia
- Coomb’s positive hemolytic anemia
- Flow cytometry shows increase in T-cell receptor positive, CD4 and CD8 negative T cells
Immune dysregulation polyendocrinopathy, X-linked (IPEX) presents with:
- IBD (inflammatory bowel disease)
- Severe eczema and food allergies
- Type 1 diabetes mellitus
- Thyroiditis
- Autoimmune hemolytic anemia
- Thrombocytopenia
IPEX
Due to mutation in ______ and loss of _________ cells
Very high ____ levels
Due to mutation in Foxp3 and loss of T-regulatory cells
Very high IgE levels
IPEX
Lab findings:
- Hypergammaglobulinemia
- Coomb’s positive hemolytic anemia
- IgE of 14,000IU/dL, skin test positive to all foods
- Low albumin, Fe deficiency
- Hyperglycemia, glucosuria, low insulin
Central Tolerance: T cells and T regulatory cell (Treg) development
- Negative selection is essential to tolerance, however some self-reactive CD4 cells are not deleted but become T-regulatory cells
- These cells express Foxp3 and suppress immune responses when activated in the periphery
HLA linkage
- Affects what peptides are presented to lymphocytes
- HLA determines susceptibility but not what diseases you will get
HLA-B27 is a strong risk factor for _______
Ankylosing spondylitis
What besides genetics needs to be considered in cases of autoimmunity
Environmental “triggers” and microbial infections
Type 1 (Immediated Hypersensitivity)
- Ig_
- T-cell type?
- Diseases?
- IgE
- T-cell type? - TH2 development
- Diseases? Allergic rhinitis, asthma, eczema, food allergies, etc…
Type 2 (Antibody mediated hypersensitivity)
General Characteristics?
Diseases?
- General Characteristics
- Antibodies are produced to self proteins resulting in disease
- Crosslinking Fc receptors on macrophage/neutrophils leads to activation and inflammation
- Phagocytosis
- Diseases
- Myasthenia gravis; graves disease
What is an aschoff Body?
Nodules found in the hearts of individuals with rheumatic fever
Acute Rheumatic Fever: J♥NES criteria
- Joints
- Heart
- Nodules
- Erythema marginatum
- Sydenham’s chorea
2 major or 1 major and 2 minor to make Dx
Duration of PCN prophylaxis for…
- Rheumatic fever without carditis
- Rheumatic fever with carditis, but without residual heart disease
- Rheumatic fever with carditis and residual heart disease
- 5 years since last episode of ARF or until 21 yr of age - whichever is longer
- 10 yrs since last ARF episode ore until age 21 - whichever is longer
- 10 yrs since last episode of ARF or until 40 years old - whichever is longer (consider lifelong prophylaxis if severe valvular disease or strep A infection)
M proteins are expressed by __________ as virulence factors
S. Pyogenes
ARF pathophysiology
Type of hypersensitivity reaction?
HLA associations for…
- African American:
- Whites:
- Native American:
- Brazilians:
Type II Hypersensitivity
- African American: HLA-DR2
- Whites: DR4
- Native American: DR3
- Brazilians: DR7
Type II hypersensitivity diseases (7)
- Autoimmune hemolytic anemia
- Pemphigus vulgaris
- Goodpasture’s syndrome
- ARF
- Myasthenia Gravis
- Grave’s diseases (hyperthyroidism)
- Pernicious anemia
Treatment of antibody mediated diseases
- Non life-threatening diseases
- Life-threatening diseases
- Non life-threatening diseases
- High dose intravenous immunoglobulin (IVIG)
- Corticosteroids
- Rituximab - kills B cells
- Life-threatening diseases
- Plasmapharesis/plasma exchange
- Basically remove plasma and antibody and replace with new
Type 3 hypersensitivity - Immune complex disease
Characteristics?
- When antigens/antibodies combine in circulation they may form immune complexes (IC)
- Activate complement and lead to clearance of IC
- Failure to clear, IC can deposit in vasculature and lead to disease
Systemic Lupus Erythematosus
- Description
- Type __ hypersensitivity
- Complement defects
- Description: Autoimmune disease characterized by auto-antibody production
- Type III hypersensitivity
- Complement defects: C1q, C2, C4 - leads to early onset SLE
SLE lab results?
- Coombs+
- Hemolytic anemia
- Low serum protein
- High creatinine
- Low serum complement levels
- Proteinuria
- High ANA
- Mutation in __, __, __ cause Neisseiria infections
C3, C4, C5
Type III hypersensitivity diseases
- SLE
- Polyarteritis nodosa
- Poststreptococcal glomerulonephritis
- Serum sickeness
- Arthus reaction
Type IV hypersensitivity diseases
Cell mediated disease (CD4/CD8)
Rheumatoid arthritis pathogenesis
Monocytes, macrophages, synovial fibroblasts activated by T cells
Three main inflammatory cytokines
IL-1, IL-6, TNF
What types of immunity contributes to the inflammatory process in rheumatoid arthritis
Both cell-mediated and humoral response
Rheumatoid Arthritis Treatment
- NSAIDS
- Anti-metabolites (methotrexate, azathioprine)
- Glucocorticoids
- Biologic therapy
- Anti-TNF agents
- Anti-IL-1 etc…
Symptoms of Dermatomyositis
- Heliotropic rash - eyelids, bridge of nose and cheeks
- Sun sensitive
- Gottron’s papules - shiny, erythematous, scaly plaques
- usually on PIP joints of hand
- Proximal muscle weakness
- Capillary changes
- Dilation, dropout hemmorhage
MAC staining in dermatomyositis (3)
- Ulex europas staining of capillaries
- C5b-9 staining showing the membrane attack complex
- Two color immunoflorescence showing MAC and capillary co-localization
Dermatomyositis - Pathology
4 parts
- Perifascicular atrophy (outside of muscle dies first)
- Perivascular inflammatory infiltrate with CD4+ T cells, B Cells, plasma cells and macrophages
- Necrosis of muscle occurs in periphery or in large groups in a wedge like fashion suggestive of infarcts
- Microvascular injury with vessel destruction leading to capillary depletion (capillary changes of nailbeds)
Polymyositis (pathology)
3 parts
- Diffuse muscle fiber death next to normal fibers
- Mononuclear infiltrates throughout fascicle
- Largely CD8 mediated
Vasculopathy (in dermatomyositis)
Capillary depletion followed by compensatory capillary dilation
Autoimmune diseases: Organ-specific
- Multiple Sclerosis - CNS motor and sensory neurons
- Thrombocytopenia - Platelets
- Guillan Barre Syndrome - Schwann cell membranes
- Hashimoto’s thyroiditis - Thyroid
- Celiac disease - Gluten enteropathy
Autoimmune Diseases: Systemic
- Systemic Lupus erthematous (SLE) - autoantibodies to dsDNA, histones, and other nuclear proteins
- Rheumatoid arthritis - autoantibodies against joint antigens
- Rheumatic fever - autoantibodies to myosin
