wk9-L15-Autoimmunity

What happens to T cells in the absence of signal 2?

○CD4+ T cell clones stimulated in vitro through TCR alone(w/o costimulation)→anergic ○In the absence of co-stimulation(signal 2)→autoreactive T cells are not triggered→no immune response is triggered

what type of hypersensitivity is seen in hemolytic anemia?

type II hypersensitivity

Describe how the baby can inherit MG from the mother

-women can pass the antibodies to the baby in the placenta→IgG is transported to the baby -baby will have MG→passive transmission -passive transfer by 6 months mum's antibodies are replaced

the immunology underlying auto-immune thyroid disease

-hashimoto's thryoiditis: ○killing thyroid by necrosis and apoptosis ○treated with supplement thyroid hormones -grave's disease: ○leads to overexpression of TSH in cells ○hyperthyroidism ○treated with radioactive iodine steroids to dampen the autoimmune response

Co-stimulatory molecules with positive and negative effects T cell activation

-2 signals are required for T cells to become activated: 1-signal 1: TCR must bind antigen presented by self-MHC 2-signal 2: T cell must undergo costimulatory engagement ○interaction between CD28 on the T cell and CD80/86 (B7) on the APC provided the costimulatory signal required for T cell activation ○CTLA-4 can also bind to CD80/86(B7): >molecule inhibits T cell activation upon binding to CD80/86(negative signal) -e.g. of immunomodulatory molecules: molecules that deliver supplementary signals during T cell activation and regulate T cell behaviour→cover costimulatory and inhibitory behaviour -CTLA-4 expression is induced only after T cells are activated

B cells develop from stem cells in the BM

-B cells which meet self antigen in the marrow are anergises -alive but unresponsive -anergised=unresponsive but not dead -must end up controlling autoreactive T and B cell

Regulatory cells help suppress autoreactivity

-CD4+ CD25+ Foxp3+ T reg cells are found in the thymus→secrete TGFβ→suppression of self reactive T cells and the few that reach the periphery are nearly all deleted -children who have mutations in FoxP3(absent) develop autoimmunity, especially to endocrine and exocrine glands ○if we take out regulatory cells→autoimmunity >increasing regulation

Theories of why some people make autoimmune responses

-Central and peripheral tolerance break down

Infections can cause autoimmunity

-Example:Epstene Bar Virus(EBV): ○EBV induces an anergic B cell to become active ○Polyclonal activation→B cell starts to make antibodies→transformed→autoantibodies →disease ○EBV associated with autoimmunity and autoimmune diseases ○persisent virus infections could lead to autoimmunity and MS

hemolytic anemia

-IgG or IgM responses to antigens located on the surface of RBCs lead to rapid destruction of these cells -antibodies against self antigens on RBCs trigger destruction of the cells→anemia -can happen in 2 ways: 1-RBCs with bound IgG or IgM antibody are rapidly cleared from the circulation by interaction with Fc or compelement receptors on cells of the fixed mononuclear phagocytic system(especially in spleen) ○antibody-complement mediated lysis→intra and extra-vascular 2-autoantibody sensitized RBCs are lysed by formation of the membrane-attack complex of complement

Cross reactivity

-infection with certain pathogens is associated with autoimmune sequelae: 1-infection 2-polyclonal antigen-specific response→lots of clones of B cells 3-one of the B cell clones produces antibodies against the infection but also binds to a self-antigen(cross reactive) 4-Auto-antibodies attack heart, joint and kindey cells →autoimmunity and rheumatic fever

evidence that there is no single pathway to autoimmunity

-to recognize foreign antigens we have to know self→fine balance between immunity, autoimmunity and hypersensitivity -evolutionary selective pressures for the IS assumed we would have procreated by 25-30yrs ago -largely own fault for living longer ○juvenile type I diabetes→in young ppl so not explained by this ○most autoimmune diseases occur in older ppl

T cell tolerance has similar mechanisms to central tolerance in developing B cells

-T cells developing in the thymus that have a high affinity for self antigen are deleted by induction of apoptosis -some of these self-reactive T cells in the thymus may be spared, and that these cells may function in the periphery as antigen specific regulatory cells

process of T and B selection is not perfect

-all have self reactive B and T cells in our body -only a few of use get autoimmune disease ○how do we control these autoreactive cells ○what triggers can allow these autoreactive cells to mature and become effector cells against our own cells and tissues?

An example of how exposure to TLR ligands can induce local inflammation

-animal model of arthritis -injection of bacterial CpG DNA into the joints of healthy mice induces an aseptic arthirtis characterized by macrophage infiltration -macrophages express chemokine receptors on their surface and produce large amounts of CC chemokines→promote leukocyte recruitment to site of injection

2 types of autoimmune diseases

-categorized depending on whether they affect a single organ or multiple systems in the body 1-organ-specific 2-systemic

autoimmune disease

-caused by failure of the tolerance processes described above to protect the host from the action of self-reactive lymphocytes -diseases result from the destruction of self proteins, cells, and organs by auto-antibodies or self-reactive T cells

What is the function of co-stimulatory molecules and their receptors in autoreactivity?

-co-stimulatory molecules and their receptors control autoreactivity -polysacharide on Dendritic cell is recognized by autoreactive T cell -CD80/86 binds to CTLA-4→autoreactive immune response

How might pathogens initiate or modulate autoimmunity?

-combination of inflammatory mediators released from activated APCs and lymphocytes and the increased expression of co-stimulatory molecules can have effects on bystander cells→lymphocytes that are not themselves specific for the antigens of the infectious agent ○e.g. self reactive lymphocytes can become activated→especially if tissue destruction by infection leads to increase in availability of the self antigen -pro-inflammatory cytokines(IL-1 and IL-6) impair the suppressive activity of Treg cells→allows self reactive naive T cells to become activated to differentiate into effector T cells→initite an autoimmune response

central tolerance limits development of autoreactive T and B cells

-deletion during early stages of maturation of lymphocyte clones that have the potential to react with self components strongly influences central tolerance -genetic rearrangements that give rise to functional TCR and Ig occur through a process where any V region gene segment can associate with any D or J gene segment→generation of variable regions that react with self antigens is almost inevitable→if this happens frequently→TCR or Ig receptors generated could produce mature functional T and B cells that recognize self antigens→autoimmune disease

Hashimoto's thyroiditis

-discovered and named after Hashimoto -patient produces autoantibodies and sensitized TH1 cells specific for thyroid antigens ○antibodies formed to a # of thryoid proteins: thyroglobulin and thyroid peroxidase→both involved in iodine uptake ○binding of auto-antibodies to proteins interferes with iodine uptake→decreased thryoid function and hypothyroidism -Delayed type hypersensitivity(DTH) response characterized by: ○intense infiltration of thyroid gland by lymphocytes, macrophages, and plasma cells→lymphocytic follicles and GCs ○inflammatory response→goiter/visible enlargement of the thyroid gland -in some cases the thryoid is destroyed -more common in women(middle age) -treatment with supplement thryoid hormones

rheumatic fever

-disease caused by antibodies elicited by infection with some Streptococcus species -antibodies cross-react with kidney, joint and heart antigens

myasthenia gravis-organ specific

-example of autoimmune disease mediated by blocking antibodies -patient produces auto-antibodies that bind the acetylcholine receptors(AchRs) on the motor end plates of muscles→blocking the normal binding of acetylcholine→inducing complement mediated lysis of cells→Ach as nothing to bind to -causes progressive weakening of the skeletal muscles→w/o treatment→severe impairment of eating and problems with movement -early signs of disease: ○drooping eyelids and inability to retract corners of the mouth -treatment=good management=normal life: ○increase acetylcholine levels(cholinesterase inhibitors) ○decreasing antibody production(corticosteroids/immunosuppressants) ○removing antibodies(plasmapheresis)

what type of hypersensitivity is immune system glomerulonephritis?

-type III hypersensitivity -treated with kidney transplants or die

Regulatory T cells in thymus

-it has been discovered recently that some self reactive T cells in the thymus may be spared and that these cells may function in the periphery as antigen-specific regulatory cells→work to dampen immune responses to the antigens that they recognize -a lot of evidence from animals and humans suggest that we are actively suppressing autoreactive cells in our body ○1970s-1980s: suppressor cells ○1990s-now: regulatory cells and cytokines →regulatory cells are a major part of the immune system -autoimmune diseases can be treated with induction of regulatory T cells and cell based therapies

Peripheral tolerance regulates autoreactive cells in the circulation

-lymphocytes with specificity for self antigens are found in the periphery -2 factors contribute to this: 1-not all self antigens are exspressed in the central lymphoid organs where -ve selection occurs 2-there is a threshold requirement for affinity to self antigens before clonal deletion is triggered→allows some weakly self-reactive clones to survive the weeding-out process

self tolerance

-mechanisms that protect an individual from an anti-self immune attack -unresponsiveness to self antigens

mice lacking CTLA-4

-mice lacking CTLA-4 display massive proliferation of lymphocytes and widespread immune disease -suggests that CTLA-4 plays an essential role in maintaining peripheral tolerance

T cell clonal deletion of self-reactive cells is not completely efficient

-millions of T cells are made every day in the thymic cortex: ○many recognise self peptides strongly(autoreactive) →have to be deleted=clonal deletion ○many do not recognise anything→die=neglect ○few recognise self peptides weakly(weakly autoreactive)→allowed to mature and leave the thymus(positive selection) -there is a grey area of autoreactive cells that manage to escape and go to the lymph nodes

systemic lupus erythematosis(SLE)

-more common in women 9:1 ratio -best e.g. of systemic autoimmune disease-multisystem immune disease -onset=20-40yrs -more frequent in African American and Hispanic women than in Caucasians -genetic component: ○MZ twins 60% more likely to have it if one twin has it ○close relatives 25x more likely to contract the disease but only 2% ever do -affected ppl produce auto-antibodies to many tissue antigens e.g. DNA,histones, RBCs,platelets, leukocytes, and clotting factors -symptoms: ○fever, weakness, arthritis, skin rashes and kidney dysfunction ○autoantibodies to RBCS and platelets→complement mediated lysis→hemolytic anemia and thromobocytopednia ○immune complexes of auto-antibodies with various nuclear antigens are deposited along walls of small blood vessels→type III hypersensitivity ○complexes activate complement system and generate membrane attack complexes and complement fragments(C3a+C5a)→damage wall of blood vessel→vasculitis and glomerulonephritis ○can also lead to seizures

Multiple sclerosis(MS)-systemic disease

-most common cause of neurologic disability associated with disease in western coutnries -occurs in women 2-3x more than men -develops during childbearing years(20-40yrs) -immune response to myelin in muscle: ○T cells can ass through BBB ○individuals produce autoreactive T cells that participate in formation of inflammatory lesions along the myelin sheath of nerve fibres in the brain and spinal cord ○causes a breakdown in the myelin sheath→many neurologic dysfunctions ○numbness in limbs, paralysis and loss of vision -chronic progressive MS→incapacitation -treatment with drugs ○2 new drugs developed ○discovery based on blocking T cell movement from brain

Lots of immune diseases are associated with HLA

-peptide and self recognition -lots of autoimmune diseases are associated with HLA types -must be a self peptide that binds to HLA -HLA is polymorphic -e.g. 99% of ppl with celiac have the HLA type HLA-DQ2→suggests that presentation of self-peptides to autoreactive T cells is important

Grave's disease(hyperthyroidism)

-ppl make auto-antibodie to thryoid stimulating hormone receptor -extremely thin -manic-ful of wild excitement -heart rushes all the time

What process produces B cells with surface receptors for self antigens?

-recombination produces B cells with surface receptors(antibodies) for self antigens e.g. they have specificity for antigen on RBC -not killed when they develop -they are tolerised→anergic ○benign but there ○all are full of autoreactive B/T cells

negative selection

-results in induction of death in some but not all cells that carry potentially autoreactive TCR or Ig receptors

Molecular mimicry

-sequence similarities between self and infectious antigens -there are similarities between our antigens/proteins and those on bacterial cells→homology -MBP→(crucial for wrapping nerves)and measles virus -HPV and insulin receptor

all of us have a population of regulatory cells in our blood

-small % of CD25+ CD4+ cells -upregulate expression of transcription factor called Foxp3 -anti CD28+ anti-CD3 cells divide and make immune response -if mixed they dont respond -TGFβ dampens the immune response

receptor editing

-some developing B cells can undergo receptor editing -antigen-specific V region is edited or switched for a different V-region gene segment via VDJ recombination→sometimes produces a less reactive receptor with an affinity for self antigens below critical threshold that would lead to disease, allowing cell to survive

What is molecular mimicry?

-some pathogens express protein or carb antigens that resemble host molecules ○antibodies produced against a pathogen epitope may cross react with a self protein ○dont have to be identical→ok if they are similar enought to be recognized by the same antibody -may also activate autoreactive naive/effector T cells if a processed peptide from a pathogen antigen is identical or similar to a host peptide→attack on self tissues -Example: ○if transgenic mice that express a viral antigen in the pancreas >normally there is no response to this virus derived self antigen >if the mice was infected with virus that was source of transgenic antigen→activates T cells that are cross reactive with self viral antigen→attack the pancreas

systemic autoimmune diseases

-the immune response is directed toward a broad range of target antigens and involves a number of organs and tissues ○reflect a general defect in immune regulation→hyperactive T cells and/or B cells ○tissue damage is typically widespread from cell mediated immune responses and from direct cellular damage→auto-antibodies or by accumulation of immune complexes

Two ways to think about autoimmune T cells

1-active suppression -controlling the autoreactive t cell with TGFβ 2-overcoming weak affinity and strong signal 2 >increase MHC, co-stimulation >nonprofessional APC→epithelial cells express co-stimulators in inflammation

Some theories of autoimmunity

1-defects in T reg cells 2-Molecular mimicry between pathogens and self peptides(antibody against streptococci cross react with heart muscle) 3-polyclonal activation of B cells during immune responses or infection(EBV) inevitably leads to some which recognise self antigens 4-sequestered antigen not seen by developing T and B cells so really just seen like a foreign antigen(sperm) →possible cause of male infertility→intolerance to sperm 5-somatic hypermuation leads to self-reactive species during affnity maturation in GCs ○B cell rearrangment to make high affinity Abs randomly

Major events that trigger rheumatic heart disease lesions

1-infection by strep→strep antigen presented on MHC class I on macrophage→induces CD4+ T cell 2-CD4+ T cell secretes cytokines→promotes B cell differentiation and clonal expansion 2-activated B cells produce anti-step antibodies 3-anti strep antibodies are similar to those that respond to antigens on the myocardium and vascular tissue so they cross-react→damage to the heart

Theories of autoimmunity

1-infections 2-cross reactivity 3-molecular mimicry 4-HLA

3 mechanisms that lead to central tolerance in developing B cells

1-receptor editing 2-clonal deletion 3-apoptosis

Microbial ligands for TLRS may also promote autoimmunity

1-stimulate dendritic cels and macrophages→produce large quantities of cytokines 2-pro-inflammatory cytokines cause local inflammation and help stimulate and maintain already activated autoreactive T and B cells -mechanism might be relevant to flare-ups of inflammation that follow infection in patients with autoimmune vasculitis→associated with anti-neutorophil cytoplasmic bodiws

TGFβ1

=an endogenous inhibitor of T cells -made by fibroblasts, epithelial cells and T reg cells -KO in mice ○animal dies of generalised T-cell mediate autoimmune disease early in life ○IL-10 made by T cells ○IL-10 knockout→colitis and autoimmune disease

autoimmunity

=inappropriate response of the immune system directing humoral and/or T cell mediated immune activity against self components -results from some failure of the host's immune system to distinguish self from nonself→destruction of self cells and organs -breakdown of self tolerance

organ-specific autoimmune disease

=the immune response is usually directed to a target antigen unique to a single organ or gland, so that the manifestations are largely limited to that organ ○cells of the target organs may be damaged directly by humoral or cell mediated effector mechanisms ○anti-self anti-bodies may overstimulate or block the normal function of the target organ

cause and increase in severity of autoimmune disease by viral or bacterial infections

Example: severity of type I diabetes in NOD mice is worsened by Coxsackie virus B4 infection -leads to inflammation, tissue damage and release of sequestered islet antigens→generation of autoreactive T cells

tolerance

a state of immunological unresponsiveness to particular antigens or sets of antigens -an organism is unresponsive or tolerant to self antigens