Microbiology - Autoimmunity

Question 1

What is Myasthenia gravis? What drug would treat this?

Answer 1

Anti-acetylcholine receptor (antagonist) Ig binding results in receptor endocytosis and degradation

fewer receptors lead to decreased sensitivity to stimulation and progressive muscle weakening.

Treat with AChE inhibitor - e.g. Neostigmine

Question 2

What is graves disease?

Answer 2

Normally, thyroid-stimulating hormone (TSH) induces the breakdown of iodinated thyroglobulin, releasing tri-iodothyronine (T3) and thyroxine (T4 ) signaling the pituitary to stop releasing TSH.

In graves disease autoantibodies bind to the TSH receptor of thyroid cells, mimicking the action of TSH so more thyroid hormones are released

Question 3

What do auto- I-antigen IgG antibodies cause?

Answer 3

autoimmune hemolytic anemia

Question 4

What causes autoimmune thrombocytic purpura?

Answer 4

auto antibodies against platelet integrin GPIIb/IIIA

Question 5

What is goodpastures syndrome? what causes it?

Answer 5

autoimmune disease associated with glomerulonephritis and pulmonary hemorrhage

auto-antibodies against non-collagenous domain of basement membrane collagen type IV

Question 6

What is pemphigus vulgaris? What causes it?

Answer 6

autoimmune dissease associated with blistering of the skin

auto-antibodies against epidermal cadherin

Question 7

What causes acute rheumatic fever? What are the symptoms?

Answer 7

antibodies against streptococcal cell wall antigens that cross react with cardiac muscle

leads to arthritis, myocarditis, late scarring of heart valves

Question 8

Defects/certain isoforms of these can affect susceptibility to autoimmunity

Answer 8

AIRE, Fas, FasL, bcl-2, TNF, FoxP3 complotypes, cytokines, signaling molecules (eg.SHP-1)

Question 9

What is the dominant genetic factor affecting susceptibility to autoimmune disease?

Answer 9

HLAs (human leukocyte antigens - human version of MHCs)

Question 10

What are major factors that contribute to development of autoimmunity?

Answer 10

1) Breakdown in central T cell tolerance
2) Breakdown in peripheral T cell tolerance
3) Breakdown in B cell tolerance

4) antigen molecular mimicry leading to detection of self antigen as foreign
5) T-regulatory cell supression

6) Release of self antigens from immonologically privileged tissues (e.g. CNS) due to trauma -

Question 11

What factors/mechanisms can lead to a breakdown in peripheral T cell tolerance?

Answer 11

Insufficient control of T-cell costimulation

Activation of naïve T cells requires both antigen presentation and costimulation (B-7/CD28)

Self cells don’t express co-stimulatory molecules so self antigens don’t activate T-cells

If T cell is activated against self antigen it will stimulate B cells to produce auto-antibodies against self-antigen presenting cells

• Autoreactive T cells may have lower threshold for activation
• Allelic variants of CTLA-4 (soluble and membrane CTLA-4 compete for binding to B-7)
• CD40, CD40L variants

Question 12

What factors/mechanisms can lead to breakdown in central T cell tolerance?

Answer 12

• Normally T cells that bind to self peptides presented by MHC on the thymic cells are deleted through negative selection
• Defects in AIRE lead to the production of a variety of autoimmune B and T cell responses, and autoimmune polyglandular diseases (thryroid, adrenal, pancreatic etc)

**AIRE = auto-immune regulating element (AIRE gene allows thymic endothelial cells to express many tissue specific antigens. It functions to desensitize auto-reactive T-cells during development and in doing so is the major facilitator of negative selection. If you pollute the AIRE, you can’t tell who is who)

Question 13

Even if negative selection works properly, some autoreactive cells do escape - why prevents these cells from becoming activated by self antigens?

Answer 13

peripheral tolerance (lack of co-stimulatory signal on peripheral tissue cells prevents T-cell activation)

Auto-reactive T cells also undergo induced tolerance from T regulatory cells

Question 14

What is central B cell tolerance?

Peripheral B cell tolerance?

Answer 14

Clonal deletion of self-reactive B cells in the bone marrow (but not all are deleted!)

• Without cognate T cell help, antigen-activated B cells in the T cell zone of a lymph node die by apoptosis
• B cells may also become anergic after encounter with soluble antigen, and then will be eliminated by antigen-specific T cell through Fas signaling.

Question 15

What is the two hit hypothesis?

Answer 15

susecptability + trigger (infection/trauma/inflammation)

Question 16

What is universal to all autoimmune disease?

Answer 16

breakdown of T and B cell tolerance and the production of autoantibody and/or inflammatory autoreactive T cells

Question 17

Type 1 diabetes is associated with what HLAs and infections?

Answer 17

Coxsackie A,B
echoviuses
rubella

HLA-DQ2,8
HLA-DR4

Question 18

How does molecular mimicry contribute to autoimmune infections?

Answer 18

Pathogen-derived peptides structurally similar to a self antigen can stimulate a T cell response directed against the self-antigen leading B cell activation and auto-antibody production

Question 19

How can infection lead to autoimmunity?

Answer 19

During infection, Class I and Class II MHC expression may be induced or increased due to interferon- gama production

e.g. Hashimoto’s disease- normally thryroid cells don’t express MHC II but infection or non-specific inflammation can lead to exposure of thyroid cells to interferon gamma, which results in expression of MHC II. T cells then recognize thyroid peptides presented on newly expressed MHC II molecules and induce autoimmune thyroid disease.

The thyroid gland in hashimotos resembles secondary lymphoid tissue, with B and T cells present.

Question 20

What is sympathetic opthalmia?

Answer 20

normally entry of naïve lymphocytes is prevented to certain sites of immune privilage such as the eye but self antigens may be exposed to circulation by wound or infection, and effector cells can gain access

Eye trauma releases antigen into surrounding tissue - makes its way to lymph node, is detected as foreign antigen, immune system is primed and effector T cells return through circulation and cause bilateral autoimmune inflammatory dissease

Question 21

Can autoimmune diseases be maternally transmitted to fetus? If so which ones?

Answer 21

IgG mediated yes b/c it can cross placenta - Hemolytic anemia, Myasthenia gravis, Thrombocytopenia purpura, Neonatal lupus

T-cell mediated autoimmune disorders are not transmitted b/c lymphocytes don’t cross placenta

Question 22

What markers are diagnostic for Systemic lupus erythematosus?

What is classic clinical sign?

Answer 22

Immune complexes contain anti-DNA, anti-nucleosome antibodies, among others
Anti-dsDNA titer is diagnostic
Specificity of response broadens over time- epitope spreading

Symptoms may include butterfly-shaped rash on face, fatigue, headaches, and glomerular damage due to immunoglobulin deposits

Question 23

What is Juvenile diabetes?

Answer 23

Type I diabetes or insulin-dependent diabetes

Beta-cells in the pancreas produce little or no insulin due to destruction by inflammatory cytotoxic CD8+ T cells.

A target antigen is glutamic acid decarboxylase (GAD)

Symptoms include increased thirst and urination, weight loss, nausea, fatigue, diabetic pancreas with insulitis (lymphocytic infiltrate)

Question 24

What causes RA?

Answer 24

Production of antibodies that react with the constant regions of other antibodies (rheumatoid factor - IgM complexes with Fc from IgG) and infiltration of the joint synovium by inflammatory CD4+ and CD8+ T cells

Question 25

What causes MS?

Answer 25

Myelin sheath covering cells of spinal cord and brain destroyed due to TH1 CD4+ T cells which secrete IFNγ and activate macrophages, also mast cell and complement activation

Autoantibodies to myelin basic protein, proteolipid protein, myelin oligodendrocyte glycoprotein

Symptoms may disappear and recur over time and include weakness, tremors or paralysis of one or more extremities, numbness, decreased memory and attention span

Question 26

What are some treatments for autoimmune diseases?

Answer 26

Physical removal of antigen, antibody or immune complexes-splenectomy (plasmapheresis)

Intravenous IgG (ivIg)- FcR effects, Ig suppression, anti-idiotype, regulatory antibodies, decrease presentation, C’ (compliment?) activation

Anti-inflammatory drugs to reduce the inflammatory response (NSAIDS, steroids)

Depletion of immune cells (azathioprine, methotraxate, cyclophosphamide; LJP394; anti-CD20-Rituximab)

Blocking interaction and/or activation of immune cells – e.g., bind to cytokines, block second signals (Enbrel-TNFα antagonist; anti-TNF-infliximab; soluble CTLA-4), BlyS, BAFF

Replacement therapy– e.g., insulin for diabetes, synthroid (Hashimoto’s)

Hormones, diet, exercise