Autoimmunity - Denzin 4/11/16 Flashcards
point of immune regulation
- avoid excessive lymphocyte activation and tissue damage during normal immune responses to pathogens and infections
- prevent inapprop immune responses and rxns specific for self antigens (self-tolerance)
TOLERANCE is a delicate balance between…
- IMMUNITY via activation : T cells (CD4, CD8), B cells, DCs, macrophages
- CONTROL via regulation : Treg, Breg, regulatory DCs, others
immunological self tolerance
specific unresponsiveness to self antigen → individual’s immune system does not attack normal body tissues
therefore…breakdown in self-tolerance → autoimmunity!
recall: types of tolerance
1. central tolerance
- selection of B cells (bone marrow) and T cells (thymus)
- apoptosis
- receptor editing (ex. B cells)
- devpt of Tregs
2. peripheral tolerance
- ignorance
- anergy/fx unresponsiveness [when no costimulation received]
- deletion/apoptosis [mediated by Fas/FasL, triggered by strong self-recognition → increased expression of pro-apop factors]
- suppression [CD4 → Tregs in thymus, Tregs mediate suppression in peripheral tissues]
T cells, selection, and self recognition
- tolerance
- fate of self-recognizing T cells
T cell devpt includes rounds of positive selection and negative selection based on self-affinity (occurs in thymus) via central tolerance
- recall: NEED T cells to be a little self-recognizing, so they can interact with MHC!, but want to keep it under control
post-selection in the thymus, there are still some self-reactive T cells → controlled by peripheral tolerance
fates of T cells that recognize self:
primary fate: apoptosis
also: both in periphery and in thymus, upregulation of FOXP3 → stimulates diff into Treg cells
- inhibit naive T cell activation
- inhibit effector T cell fx
hit T cell fx at every level of maturation!
Treg cells
phenotype
- CD4+
- IL2 receptor HIGH [CD25]
- IL7 receptor LOW [CD127]
- FOXP3+
- GITR+
significance: IPEX (immune dysfx, polyendocrinopathy, enteropathy, X-linked)
- early onset, insulin-dep diabetes (type I)
- severe watery diarrhea
- failure to thrive
- dermatitis
mechanisms of Treg function
therapeutic role???
multiple!
- tons of cytokines (inhibitory and otherwise)
- metabolic disruption (ex. sequestration of IL2, required for T cell survival)
- targeting DCs
therapeutic potential : if we can induce or activate Tregs in immune diseases, might be able to get them under control
-
risks
- Uissues with numbers, specificity, stability
- nonspecific immune suppression, potential to turn into pathogenic T cells themselves (low stability)
Q: how do tissue-specific gene products get expressed in the thymus for T cell selection to take place?
role of autoimmunity
idea: if tissue-specific genes arent being expressed in thymus, youre only going to be able to select for T cells during devpt with a very small (incomplete) subset of proteins
- autoimmunity (APC aka APECED) played a role in answering this Q
APS gene → AIRE (autoimmune regulator)
-
mediates ectopic gene expression in thymus → turns on genes that normally wouldnt be turned on in the thymus → lets the T cell repertoire undergo selection against other proteins
- highlights importance of T cell central tolerance in controlling autoimmunity!
B cells, selection, and Bregs
some self-reactive B cells escape central tolerance mechanisms → have to be controlled by peripheral tolerance
- deletion or anergy [high avidity binding]
- regulation by inhibitory receptors [low avidity binding]
- Breg suppression of B cell responses [v poorly understood]
autoimmunity
- definition
- how it’s caused
relating to/caused by antibodies and/or T cells that attack molecules/cells/organs of tissues producing them
typically arises spontaneously, involving some of the following:
- reduction/loss of Treg activity
- normal self antigens modified by drugs, environmental chemicals, viruses, mutations → look like non-self, and are attacked
- “molecular mimicry” : exposure to antigen that looks v similar to self antigen → leads to activation of self-reactive T cells
2 major patterns of autoimmune disease
1. organ specific autoimmune diseases
-
restricted to a few specific tissues: autoantigens from a few specific organs are recog’d → disease is ltd to these organs
ex. Type 1 DM; Hashimoto’s, Graves; Addison’s; Sjogrens
2. systemic autoimmune diseases
-
involves many tissues/organs: autoantigens are ubiquitous, found everywhere (DNA, cell surface mols, intracellular matrix proteins) → disease affects whole body
ex. rheumatoid arthritis, lupus, scleroderma; often diseases affecting connective tissue or vasculature
genetic basis of autoimmunity
- runs in families
- increased incidence in twins (more in identical ones)
- disease-associated genes exist
-
major association : MHC genes (certain haplotypes have strong assoc with autoimmunity)
- DR2 - multiple sclerosis
- DR1/DR4 - rheumatoid arthritis
- DQ2 - Celiac disease, DM1
-
major association : MHC genes (certain haplotypes have strong assoc with autoimmunity)
multiple genes associated with autoimmunity
- most human autoimmune diseases are multigenic
- single gene defects reveal pathways (ex. AIRE, FOXP3)
most diseases have multiple genes contributing to them
- genome wide assays can link genes to disease
- some genes are implicated in many diseases
- some genes are implicated in only one disease → evidence for distinct mechs of disease
- in most cases, the causative genetic variations have not been identified
what else (besides genetics) affects autoimmunity?
environmental factors
- examples
- NOD mice
genetics cant explain it all!
environmental factors
ex. NOD mouse - DM1
- NOD mice are inbred → most are genetically destined to get DM1
- there’s lots of variability in time of onset and actual pathogenic aspects of onset from investigator to investigatoe → environment must play a role
environmental factors could include drugs, UV rays, other things that lead to some kind of aberrant cell death and release of self antigen → activates autoimmune response
*
what else (besides genetics) caffects autoimmunity?
infection
1. molecular mimicry
immune system responds to a pathogen that somehow has a protein/antigen that LOOKS LIKE SELF ANTIGEN
- activated T cells and antibodies from B cells cross react with self antigens → autoimmunity
ex.
group A streptococcal M protein ~ antigen in cardiac muscle : molecular mimicry might play a role in rheumatic fever
2. bystander activation : infection provides ideal environment for autoimmunity
disruption of cell/tissue barriers can lead to release of sequestered self antigen → activation of non-tolerized cells → autoimmunity
ex. in NOD mice, severity of DM1 is exacerbated by Coxsackie virus
* infection → inflammation, tissue damage, release of sequestered self islet antigen → generation of self-reactive T cells
autoimmunity is far more common in developed world than in undeveloped world
why?
hygiene hypothesis
excessive protection from exposure to dirt/pathogens in early childhood can stunt devpt of immune system
- potentially increased prevalence of asthma and autoimmunity in developed world
- MAYBE…no direct evidence
important to keep in mind bc introduces a caveat to infection/autoimmunity connection:
infection can exacerbate autoimmunity, but some infections can all help prevent autoimmunity!
autoimmune diseases can be triggered by drugs
- immunological response : drug hypersensitivity
- rxn to native form of drug or some metabolite of it complexed with host protein
- usually reversible
- drug-induced autoimmunity
- progresses indep of drug withdrawal
- needs some form of immunosuppressive treatment
ex. Abacavir hypersensitivity syndrome (AHS)
- avacavir is an antiretroviral used to treat HIV → induces a fatal hypersensitivity in patients with a specific HLA
- HLA-B57:01 type ends up putting a protein that wouldnt normally be on the surface out on the surface → induces immune response
autoimmune diseases tend to be chronic
in most cases, the initiating antigen cant be eliminated
plus, the immune system contains several built in amplification mechs intended to optimize the immune response
“epitope spreading” occurs when the immune response starts in resp to one antigen → spreads to many other antigens
postulated mechanism for autoimmunity
genetic susceptibility
- susceptibility genes → failure of self-tolerance → production of self-reactive lymphocytes
presentation of antigen
- could be via infection/injury/drugs
- could be via experession of citrullinated proteins you might not otherwise see
activation of APCs → activation of self-reactive lymphocytes → autoimmunity!
specific mechanisms for…
lupus
rheumatoid arthritis
