autoimmunity Flashcards
what is immunological tolerance
unresponsiveness to an antigen that is undiced by previous exposure to that antigen
the same antigen by induce an immune response/tolerance depending on the conditions of exposure and the presence/absence of other stimuli
what are tolerogens
antigens that induce tolerance
what is self-tolerance
tolerance to self-antigens
fundamental property of the normal immune system
failure of self-tolerance results in immune reactions against autologous antigens - autoimmunity
how is immunological tolerance achieved
diversity of T cell antigen receptors and immunoglobulin molecules
many antigen-specific receptors capable of binding to self-molecules
to avoid auto-immune disease - T and B cells bearing self-reactive molecules must be eliminated or downregulated
central and peripheral tolerance
what is central tolerance
the thymus plays an important role in eliminating T cells w/ high affinity to self antigens
bone marrow is important in B cell tolerance
how do regulatory T cells develop
CD4 +ve and CD8 +ve cells w/ minimal or low affinity to self antigens may go on to develop into regulatory T cells
affinity to self-antigens in an inhiibitory fashion
peripheral tolerance
mature lymphocytes that recognised self-antigens in peripheral tissues become incapable of activation or die by apoptosis
anatomic barriers - self-antigens sequestered from immune system e.g. DNA inside nucleus, blood brain barrier
anergy: antigen recognition w/o co-stimulation - T cell functions require both stimulation and co-stimulation to become effector cells - functional unresponsiveness
Treg supression
deletion - cell death
how can the peripheral tolerance be overcome
inappropriate access of self-antigens
inappropriate or increased local expression of co-stimulatory molecules
alterations in the ways in which self-molecules are presented to the immune system
when is peripheral tolerance more likely to be overcome
when inflammation/tissue damage is present due to the increased activity of proteolytic enzymes
intra and extracellular proteins broken down
high concentrations of peptides presented to responsive T cells
structures of self-peptides may be altered by viruses, free radicals or ionising radiation - bypasses previously established tolerance
how does autoimmune disease arise
‘normal’ autoimmunity at low levels from auto-reactive T cells
can be broken due to multi factors - multi-hit method
- through genetic predisposition, exposure to infection, environmental factors
breakdown of immune tolerance –> autoimmune disease
define autoimmunity
adaptive immune responses to self antigens
occurs when autoreactive T cells/autoantibodies cause tissue damage through hypersensitivity reactions (types II, III, IV)
what are autoantibodies
antibodies directed at normal cellular components - referred to as autoantigens
most healthy individuals produce some autoantibodies - very low level and low affinity
where are natural antibodies secreted from
B1 cells secrete natural antibodies that are the major source of autoantibodies
what do natural antibodies bind to
bind w/ low affinity to antigens on a variety of bacteria
this activates complements and helps clear invading bacteria rapidly
can also bind to normal cellular constituents such as nuclear proteins and DNA
what do natural antibodies cross react with
cross react w/ the inherited A and B antigens of red cells
unless they have inherited either A or B antigens, individuals make anti-A and anti-B antibodies, even if they have never been exposed to red cells from another person
natural antibodies in SLE
reactivity is against DNA
DNA is available in every cell
when there is breakdown of tissues (infection, trauma, UV light) this could cause exaggerated immune response against the DNA
what causes breakdown of T cell tolerance
genetic predisposition
environmental factors
how does breakdown of T cell tolerance develop
multi step mechanism
patient inherits different traits e.g. HLA w/ poor binding for self antigens; genetically poor expression of certain self antigens in the thymus - the T cells which react to these aren’t eliminated in the thymus - autoreactive T cells escape into the periphery
peripheral tolerance is broken - effector autoreactive T cells which are capable of causing tissue damage in self tissues
symptoms present
T cell breakdown diagram
genetic predisposition - don’t express self antigens
autoreactive T cells don’t form
autoreactive T cells aren’t going to bind w/ high affinity and escape into the periphery - mechanisms of peripheral tolerance should deal w/ them
if peripheral tolerance breaks down then T cells aren’t cleared and are able to cause autoimmunity
if the suppressive function of regulatory T cells is missing, then auto-reactivity and auto-immunity could progress
patterns of genetic factors that lead to auto-immunity
clusters within families
alleles of MHC
common polymorphisms are implicated in the breakdown of immune tolerance that leads to these diseases
some rare genetic diseases cause autoimmunity
AIRE gene is mutated and central tolerance cannot take place
genes related to autoimmunity
- HLA association
- disease
- relative risk
B27 - ankylosing spondylitis - 85, reiter disease - 37
DR2 - good pasture syndrome - 16
DR3 - Sicca syndrome - 10, Addison disease - 9, Hashimoto thyroiditis - 3, myasthenia gravis - 3
DR4 - IDDM - 6
what environmental factors can enhance auto-immune reactions
INFECTIONS:
- molecular mimicry
- upregulation of co-stimulation
- antigen breakdown and presentation changes
DRUGS:
- molecular mimicry
- genetic variation in drug metabolism
UV RADIATION:
- trigger for skin inflammation
- modification of self-antigen
what is molecular mimicry
structural similarity between self-proteins and microbial antigens may trigger an autoimmune response
Group A streptococcal protein
- self-antigen w/ similar structure
- disease in which consequent molecular mimicry may play a role
antigen found in cardiac muscle
rheumatic fever
types of AI diseases
organ specific vs non-organ specific
location of the antigen determines where a disease lies in the spectrum
autoimmunity in T1DM
normal cells in islets of langerhans are free of T cells, no inflamamtion or infection
if there is a problem w/ central tolerance e.g. antigens for islets are poorly presented in thymus, there won’t be highly reactive T cells
T cells which are reactive to the islets escape the central tolerance and get to the pancreas - not a problem (no co-stimulation even if they bind to antigens, no effector function against the islets)
if the regulatory T cells are defective, then they won’t suppress the reactive cells and they can then cause damage
any infection/inflammation will mean enhanced antigen presentation
autoimmunity in SLE
auto-antigen is the DNA
infection/inflammation leads to breakdown of lots of cells - DNA leaks out
if not contained by the complement system it may give AI in the patients who have a genetic susceptibility
IgGs against DNA start being produced and binding to DNA - immune complexes start forming
complexes start precipitating in different parts of the body and cause damage
treatment of AI disease
suppression of the damaging immune response
replacement of the function of the damaged organ
