liveonearth (liveonearth) wrote,

Immunology: Autoimmunity

Study Questions:
1. What influences the pathology of autoimmune disease?
2. What’s the difference between type II and type III autoimmunity?
3. What autoantigens are involved in lupus?
4. What cells are destroyed in diabetes? What cells do the destroying?
5. Is MS more prevalent in men or women?
6. What do oligodendrocytes do? Why do CD8’s kill oligodendrocytes in MS?
7. What cytokines are involved in Rheumatoid arthritis?
8. What is rheumatoid factor?
9. What causes joint destruction in RA?
10. Why does RA affect both hands and not just one?
11. Which botanicals or probiotics could help RA? (bonus question: look at lecture 6)

1. The antigen that is the target of the response (i.e. insulin = diabetes; MBP = MS), mechanism of destruction (T cell vs Ab)
2. Type II is Ab to a cell surface antigen whereas Type III is Ab to a soluble self antigen
3. DNA, nucleosome, spliceosome, ribonucleoproteins: Ro and La
4. β-islet cells; CD8 T cells
5. women (3:1) also happens more the farther from the equator you go in either direction
6. Oligodendrocytes make MBP (myeline basic protein) to coat the axon with the myelin sheath. MBP is endogenous and therefore presented in MHC class I. CD8's specific for MBP will kill cells presenting MBP in MHC class I.
7. IL-1 and TNFα
8. IgG anti-IgG (antibody that is specific for the Fc constant region of self IgG)
9. TNFα and IL-1 (mainly TNFα, all three of the popular treatments are anti-TNFα)
10. Immune response is systemic.
11. fish oil and probiotics (esp bifidus) will reduce Th1 and Th2 response, probiotics work by pushing a Th3 tolerance response

Autoimmunity Outline:

I. General Principles of Autoimmunity
A. Factors that Affect Autoimmunity
B. Classification by Immunopathogenic Mechanism

II. Diabetes
A. Heredity
B. Disease mechanism

III. Multiple Sclerosis
A. Epidemiology
B. Blood Brain Barrier
C. Disease mechanism

IV. Rheumatoid Arthritis
A. Heredity
B. Disease Mechanism
C. Rheumatoid Factor

--autoimmunity is an immune response to self tissues
--problem: you can't clear self (and remain healthy)
--cause: we don't know
--often associated with infection which provides costimulation
--new antigens and molecular mimicry also implicated

A. Factors that effect autoimmunity
--environment, internal vs external: both play a role
--heredity: twin studies show 20% of monozygotic (identical) twins show disease concordance
--since it's not 100% in monozygotic twins, environment must play a role
--less than 5% of dizygotic twins raised together show disease concordance
--since 20% in monozygotic is 4x the 5% in dizygotic, heredity (genetics) must play a role.
--very different pathology depending on antibody or T-cell mediated

--classified like hypersensitivity reactions;
--there is no Type I because there is no IgE specific for self

--Type II is IgM or IgG specific to self cell surface antigen, three possible mechanisms
--mech 1: antibody kills cells via Fc Receptor on Macs, Mast Cells, or NKs, or via C'
--example: autoimmune hemolytic anemia
--mech 2: antibody blocks receptor
--example: Myasthenia Gravis: antibody to nicotinic acetylcholine receptor on skeletal muscle → blocks neuromuscular transmission → weakness
--mech 3: antibody stimulates receptor
--example: Graves Disease: antibody to TSH receptor blocks feedback loop → stimulates production of TSH → hyperthyroid

--Type III is IgM or IgG to soluble self antigen
--large amount of antigen → large amount of immune complexes (ab bound to antigen) → overwhelm normal clearance mechanisms → complexes lodged in capillaies esp in kidneys and skin → damage to surrounding tissue
--exmple: bacterial endocarditis-- bacteria on cardiac valve → immune response to bacteria causes immune complexes → damage to kidney and skin → cells release autoantigens
--example: systemic lupus erythmatoses (SLE)-- autoantigens: nucleosome, spliceosome, ribonuclesprotiens Ro and La, anti-DS-DNA (an ANA)
--proteins released when cells die → response to them activates phagocytosis → more tissue damage → more immune complexes

--Type IV is T cell mediated
--ex: type I Diabetes (IDDM)
--certain types of MHC are predisposing: HLA-DR3 & HLA-DR4, HLA-DQ
--HLA-DQB1*0302 has no aspartate as position 57-- binds insulin really well! → high chance of IDDM
--protective MHC type: HLA-DR2 (same one that increases risk of MS)
--mechanism: CD8 T cells specific for insulin escape tolerance → CD8's for insulin get activated by APCs presenting insulin (caused by infx?) → CD8 T cells kill β-islet cells
--CD8's can also be specific for GAD (glutamic acid decarboxylase) or 38Kda secretory granule
--GAD converts Glutamic acid to GABA → GABA triggers release of insulin from granules
--CD4's and B cells also involved-- some of the same antigens

III. Multiple Sclerosis (MS) causes numerous areas of demyelination within the brain and spinal cord without axonal degeneration
--7:1 prevalence in women
--pregnancy (progesterone) shuts down disease
--age of onset is typically 25-30 yrs.
--incidence is dependent upon latitude: closer to poles, more MS, near equator, less MS
--highest incidence is in Canada; Norway, Sweden also high
--not race related because native Australian (close to the south pole) also high incidence
--Tends to effect high socio-economic groups
--Caucasians more susceptible
--HLA-DQ B1 found in high prevalence in Norwegians confers susceptibility
--HLA-DR2 is more capable of presenting MBP (myelin basic protein) and PLP (proteolipid protein) (this is the same HLA that decreases risk of IDDM)
--mechanim: MBP is presented to T cells with costim due to infx?? → activates MBP specific T cell that escaped tolerance in thymus → CD4 T cells activate MBP specific B cells to secrete IgG → IgG binds to MBP → Macs bind IgG with FcγR and destroy myelin sheath → Oligodendricytes produce more myelin to re-cover the sheath → CD8 T cells kill oligodendricytes
--CD4s important for disease pathogenesis early; CD8's important late
--Conditioned healing of EAE (mouse MS): alpha lipoic acid (ALA) abrogates disease
--Give mouse MS → Give ALA + saccharin (sweet taste) → remove ALA and give saccharin alone → mouse heals from EAE

IV. Rheumatoid Arthritis (RA) = a multi-system chronic inflammatory disease affecting peripheral joints in a symmetric fashion leading to cartilage destruction, bone erosion, and joint deformities
--incidence: more women than men by 3:1
--Estrogen triggers higher production of TNF by macrophages
--HLA-DR4 and HLA-DR1
--β-chain of MHC must contain amino acid sequence LLEQK(L or R)AA in position 67-74
--confused by the lack of a definable antigen: HSPs? Collagen?
--γδ T cells involved → make high levels of IFNg → B cells produce IgG (involved in RF)
--both αβ and γδ T cells release cytokines that bring in macrophages, neutrophils → macs and neutrophils release ROS, TNF, and IL-1b → damage cartilage
--TNF and IL-1β present in high levels in the joint of an RA patient
--synovial fluids containing these cytokines injure normal cartilage in vitro
--that damage can be prevented by specific cytokine inhibitors
--recombinant (synthesized) IL-1 or TNFα damages normal cartilage in vitro & in vivo.
--Progression of RA may be prevented with inhibitors of IL-1 and TNFa

C. Rhematoid Factor (RF)
--IgM anti-IgG or IgG anti-IgG (i.e. IgG is the antigen)
--Ab binds to Fc region of other Ab
--IgM response when there is no T cell help
--get T cell help and make IgG anti-IgG
--RF doesn't look like it damages tissue (i.e. if you take it from one person or mouse and inject into a second person or mouse, the recipient doesn't get arthritis)
--RF is present in 60% of RA cases and is not diagnostic alone
--mechanism: Ab's bind to Ag → Ab's bind to Ab's forming complex → floats around, gets stuck in narrow place → Neuts, eos, basos, and macs engulf Ab/Ag complexes → release granules → ROS, leukotrienes, Prostaglandins → destruction of joint
Tags: arthritis, autoimmune, diabetes, immunology, rheumatoid

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