Tolerance and Autoimmunity Flashcards
What are the central and peripheral fates of lymphocytes that recognize self antigen?
Central Tolerance:
- Apoptosis (deletion)
- Change in receptors (receptor editing: B cells only)
- Development of regulatory T lymphocytes (CD4+ T cells only, express Foxp3 and suppress immune response)
Peripheral Tolerance:
- Anergy (inactivation)
- Apoptosis (3 mechanisms; Fas/Fas ligand, cytokine withdrawal, AICD)
- Suppression (e.g. by T regulatory cells)
What is AIRE?
What results when there is a defect in AIRE?
“AutoImmune REgulatory gene” is a transcription factor that induces expression of self-antigens by the thymic medullary epithelial cells. **key to negative selection
**When AIRE is lost:
- Self reactive T cells are not deleted
- Self reactive T regulatory cells are not generated
- Autoimmunity occurs (APECED; example of failure of central tolerance)
What two signals are needed for lymphocyte activation?
- T cell receptor sees an antigen on MHC
- Co-stimulation; CD28 ligation by B7-1 (CD80) and B7-2 (CD86) on antigen presenting cells
What is the result of antigen presenting cells that lack co-stimulatory molecules?
APCs lacking B7 promote anergy (the functional inactivation of lymphocytes)
Contrast CD28 and CTLA-4
Both are on the T cell and bind B7-1 (CD80) and B7-2 (CD86)
CD28 is the activating receptor
CTLA-4 is the inhibitory receptor and binds B7 with higher affinity (Abatacept= recombinant CTLA-4 for autoimmunity)
What is PD-1?
A checkpoint inhibitor induced in T cells
*Targeted in cancer
What induces B7 molecules? What is the result if an APC lacks B7?
Microbes induce B7 molecules on APCs by recognition of PAMPs by TLRs/NOD receptors
Without B7 (or with B7 engagement of CTLA-4), anergy/unresponsive T cells result
What are the mechanisms of T/B cell death after an immune response?
- AICD (activation-induced cell death) from repeated activation of mature T cells by self antigens
- Fas/FasL (potent actiator of apoptosis); CD4+ T cell activation upregulates expression of Fas “death receptor”
- Cytokine withdrawal; properly activated T cells express IL-2 (growth/survival factor). Lack of IL-2 when immune stimulus is gone results in apoptosis
What is the result of mutation in Fas/FasL?
ALPS (autoimmune lymphoproliferatice syndrome); example of failure of peripheral tolerance
*High levels of IgG, IgA, IgM, and double negative (CD4-/CD8-) T cells common
What is Foxp3?
Transcription factor expressed by T regulatory cells
Where are T regulatory cells generated? How/where are they activated?
Generated by self antigens in the thymus (remember AIRE), activated in the periphery by self antigen and IL-2
How to T regulatory cells suppres the immune response?
-
Contact Dependent; Treg binds directly to mature T cells, inducing inhibitory signaling
(e. g. CTLA-4, surface bound TGF-beta, killing of targets through perforin and granzyme) - Contact Independent; Tregs secrete TGFbeta/IL-10 that inhibit T cell activation
What is the result of lacking T regulatory cells?
IPEX (immune dysregulation polyendocrinopathy enteropathy, X-linked)
*Foxp3 mutation, affects boys in infancy
*Autoimmune, very high IgE levels
What characteristics of an antigen may contribut to tolerance or the breakdown of tolerance?
Location, abundance, and persistence of antigen
How does genetics affect our ability to respond to foreign and self tissue?
HLA affects what peptides are presented to lymphocytes
*Having certain HLA alleles increases relative risk of developing certain autoimmune disorders
Also many other genetic susceptilibility loci (AIRE, complement proteins, Fas/FasL, Foxp3, IL-2, etc)
What role do environmental factors play in autoimmunity?
In some cases infection can trigger autoimmunity in a susceptible person
**The infectious organism could have antigens that look like self resulting in autoimmunity (molecular mimicry)
Summarize type 1 hypersensitivity
- Immediate hypersensitivity
- Requires TH2 development
- IgE mediated
- E.g. allergic rhinitis, asthma, eczema, food allergies
Summarize type 2 hypersensitivity
**Antibody mediated hypersensitivity
- Crosslinking Fc receptors on macrophages/neutrophils
- > inflammation
- Complement activation -> inflammation
- Phagocytosis promoted by IgM and IgG
- Function blocking/activating Abs (e.g. myathenia gravis)
What are the JONES criteria?
For acute rheumatic fever (a type II hypersensitivity reaction and an example of molecular mimicry):
Joints
Heart
Nodules
Erythema marginatum
Sydenham’s chorea
What are the treatments of antibody mediated disease?
Non-life threatening disease:
- High dose IV immunoglobulin (IVIG); competes for Fc receptors and activates inhibitory Fc receptor
- Corticosteroids (prednisone); anti-inflammatory
- Rituximab (anti-B cell therapy)
Life threatening disease:
- Plasmapheresis (rare)
Summarize type 3 hypersensitivity
Immune complex deposit in vasculature leads to disease (antigen + antibody= IC, normally activate complement and are cleared)
e.g. systemic lupus erythematosus from complement defects
*injury mainly from leukocyte recruitment and inflammation
Summarize type 4 hypersensitivity
Cell mediated disease (CD4/CD8);
- TH1 mediated hypersensitivity reaction
- TH17 mediated inglammatory reaction
- Kiling of host cells by CD8+ CTLs
*Delayed response
What is the pathology of arthritis?
- T cells in synovial spaces are self reactive
- Monocytes, macrophages, fibroblasts are activated by T cells -> release IL1, IL6, TNF -> inflammation
- Panus formation; aggregates of mononuclear cells (T/B cells, macrophages)
**both cell-mediated and humoral immune response contributing to inflammation
What are the common treatments for arthritis?
- NSAIDs
- Anti-metabolites (inhibit DNA synthesis; e.g. methotrexate and azathioprine)
- Glucocorticoids
- Monoclonal Ab to immune molecules (e.g. anti-TNF, anti-IL1/6, etc)
Define hypersensitivity reaction
Immune response that causes tissue injury (may arise from uncontrolled/abnormal response to foreign antigen or an autoimmune respons against self antigen)
