29- Autoimmunity Flashcards
what is autoimmunity?
when the body’s immune system mistakenly targets and attacks its own cells/ tissues/ organs
what is immune tolerance?
the immune system knowing what to and what not to attack
doesn’t attack self-proteins/ cells as it’s tolerant to them through various regulatory controls
what are the two types of tolerance?
central
peripheral
what is central tolerance?
the removal/ elimination of self-reactive T/ B cells at the site of production/ before they enter circulation
what is peripheral tolerance?
the removal of self-reactive T/B cells that have escaped into circulation - cells that have avoided central tolerance mechanism
describe central tolerance in B cells
immature B cells in the bone marrow encounter self-antigens - if their surface IgMs bind and cross-link the self-antigens = B cell undergoes apoptosis
ensures no self-reactivity, and B cells that mature and develop only recognise foreign antigens, and tolerate self-antigens
how do T cell influence B cell class switching?
APCs present peptide-MCH 2 complex to naïve CD4+ T cell - TCR recognises complex and activates
cytokine environment (IL-4, 5) influences differentiation of naïve Th cell into Th2 cell
Th2 cell then interacts with B cell BCR which is also presenting a peptide-MHC 2 complex = activates Th2 cell
CD40L on Th2 cell binds with CD40 on B cells - effects:
- induces a specific type of Th2 cytokine production to influence antibody class switching
- CD40L-CD40 interaction induces AID expression in B cells which is important for class-switching recombination
different isotope antibody is produced with the same specificity following class-switching recombination - e.g. from IgM to IgG / IgA/ IgE
what are the main steps in T cell influence on B cell antibody class switching?
differentiation of naïve T cell to activated Th2 cell
Th2 cells recognise antigen presented by B cell BCR
CD40L on Th2 interacts with CD40 on B cell - induces specific cytokine secretions by Th2 cells to direct class switching, and activate AID enzyme for class-switching recombination = change in antibody class
how does T cell central tolerance work?
positive selection - immature T cells expressing TCRs must recognise self-MHC molecules with moderate affinity
negative selection - immature T cells that bind too strongly to self antigens presented by MH molecules by thymic epithelial cells, macrophages or dendritic cells undergo apoptosis = eliminates self-reactive T cells
- AIRE expression allows expression of tissue-specific antigens not found in the thymus = thymocytes exposed to a wide range of self-antigens from different tissues, increases effectiveness
regulatory T cells - some self-reactive T cells instead differentiate into regulatory T cells = maintain peripheral tolerance, suppress unnecessary immune responses against self-antigens or without cause
how does T cell central tolerance link to rheumatoid factor?
central tolerance mechanisms that fail to destroy self-reactive T cells - these T cells escape into peripheral blood and recognise self-antigens of IgG
RF of IgM is expressed at low levels, but in autoimmune conditions like rheumatoid arthritis RF of IgG is expressed at high levels, causes a problem
self-reactive T cells recognise RF-IgG = immune complexes formed, complements activated, induces B cell response = promote autoimmunity associated with rheumatoid arthritis by attacking synovial joints (site of immune complex deposition)
failing central tolerance of T cells = influences B cells and autoantibody production
what is rheumatoid factor?
an autoantibody that targets the Fc region of IgG antibodies
associated with autoimmune diseases - esp. rheumatoid arthritis
presence is linked to failure in central & peripheral tolerance
describe rheumatoid expression in rheumatoid arthritis?
normally rheumatoid factor of the IgM class - low expression
IgM to IgG class switching under T cell influence
rheumatoid expression of IgG can be pathogenic, higher expression - RF of IgG forms immune complexes with IgG antibodies
immune complexes deposited in synovial joints, activate complement cascade, macrophages and B cell responses
cause inflammation, tissue damage within joints = autoimmunity of rheumatoid arthritis
what is an autoantibody?
antibody that react with self-antigens
describe positive selection in T cell central tolerance
in thymic cortex:
if TCR binding to self-MHC is too weak - insufficient signalling strength when binding to MHC with foreign peptides = apoptosis
if TCR binding to self-MHC is too strong - may allow signalling irrespective of whether there’s aa self/ foreign peptide in the groove = apoptosis
binding needs to be of moderate affinity - capable of binding and recognising self-MHC = survival signal!
what is the importance of AIRE in T cell selection?
autoimmune regulator - specialised transcription factor that allows expression of all genes/ tissue-specific genes not found in the thymus to developing T cells in the thymus
AIRE mutations result in multi-organ autoimmunity/ many autoimmune conditions
what are the three mechanisms for maintaining peripheral tolerance?
ignorance
anergy
regulation
how does ignorance maintain peripheral tolerance?
relies on the fact that self-reactive T/B cells don’t encounter self-antigens from specific peripheral tissues, or the antigen is in too low of a concentration to trigger a response
- e.g. eye and brain = immunologically privileged sites, tissue-specific antigens not often encountered
what is anergy in lymphocytes?
the state of functional unresponsiveness of T/B cells to antigen stimulation
self-reactive lymphocytes that encounter self-antigens in the absence of co-stimulatory signals become anergic
how does anergy maintain peripheral tolerance?
naïve T cells need 3 costimulatory signals in order to become fully activated
if a naïve T cell recognises a self-antigen but isn’t fully activated by the appropriate stimulatory signals = becomes anergic
enters a state of functional unresponsiveness, less likely to be activated in the future even if all the costimulatory signals are present
without adequate co-stimulation - T cells fail to proliferate and produce effector cytokines; B cells fail to differentiate into plasma cells and secrete antibodies
what are the three costimulatory signals required for full T cell activation?
recognition of peptide-MHC class 1 or 2 by TCR = TCR interacts with complex
co-stimulation between CD28 on T cell and member of the B7 family – CD80/86 on APCs = activation
cytokines are produced that can modulate/ influence how the naïve T cell develop or responds – e.g. CD4+ T cell developing into Th1 or Th2 cell
how does regulation maintain peripheral tolerance?
T regulatory cells maintain peripheral tolerance by dampening immune response
T cells express FoxP3 transcription factor - suppresses activation of T cells by secreting immunosuppressive cytokines - IL-10, TGF-beta
cytokines inhibit autoreactive T cell effector function and cytokine production - prevents autoimmune responses
