1AutoimmunityRobert BeattyMCB150Autoimmunity is an immune response toself antigens that results in disease.The immune response to self is a result of abreakdown in immune tolerance.What is Autoimmunity? Immune ToleranceTolerance of self is a hallmark of adaptiveimmune response.B cell tolerance vs. T cell tolerance.B cell ToleranceNo T cell helpAutoreactive B cells that enter lymph node should fail to get costimulation from T cells and therefore never enter primary follicles.2Maintenance of T cell toleranceClonal deletion– negative selection in the thymus, deletion in theperiphery.Sequestration of antigens– Inside nucleus– Inaccessible to immune system (brain, eye, testes)Immunological ignorance– self antigens at low density on APCs– or T cells do not cross barrier.Maintenance of T cell toleranceAnergy– Lack of co-stimulation or second signal to Tcells results in anergy.Suppression– T-cell cytokine mediated suppression.– Regulatory T cells. CD4+CD25+ CTLA4+T cells that produce suppressive cytokines.Inducing Autoimmunity ORBreaking of self-toleranceInjury (inflammation)orInfection"Viral Trigger" is term for virus infectionleading to autoimmune response.Inducing Autoimmunity3Breaking of self-toleranceRelease of sequestered antigens: Tissuedamage by infection may allow access of Tcells and B cells to sequestered antigens.Antigenic (molecular) mimicry is whensimilarity between foreign antigen and selfprotein results in cross-reactivity.Antigenic MimicryBreaking of self-toleranceInappropriate expression of Class II MHC.– Abnormal expression of class II molecules canlead to presentation of self antigens that werenot presented in thymus or periphery.– "non-APC" becomes APC with inflammation.Classification ofautoimmune diseasesAutoantibody orT cell mediatedautoimmune diseases4Autoantibody mediated diseases Autoimmune hemolytic anemia antibodies to rbc antigensIgM abs against CHO on rbc cell surface binds– causes C' activation and lysis– phagocytic cell clearanceAntibodies to rbc antigens Autoimmune hemolytic anemiaIgM abs thought to be from infection– Mycoplasma or Epstein Barr virus thought to beassociated.– Can be transient as long as you have infection.– Unclear how exactly triggered.Autoantibodies to surface receptors Graves' disease =hyperthyroidStimulating autoantibodies bind thyrotropin receptor for thyroid stimulating hormone.5 Antibodies to acetyl choline receptors block muscle activationand trigger Inflammation that causes the destruction of thenerve/muscle junctions resulting in paralysis.Myasthenia Gravis Blocking AutoantibodiesAutoantibodies to surface receptorsBlocking autoantibodies  Hashimoto's thyroiditis =hypothyroidBlocking autoantibodies inhibit thyroidfunction.Goodpasture's SyndromeAutoantibodies to type IV collagen and non-collagenous basement membrane.Antibodies bind in lung and kidney causinginflammation and destruction.Increased risk with smoking.Rheumatoid ArthritisImmune Complex DiseaseAutoantibodies to ubiquitous antigens– IgM against IgG is called "rheumatoid factor"– IgG against glucose-6-phosphate isomerase.Primary disease manifestation– immune complexes get deposited in joints and triggerinflammatory response through complementactivation and binding FcγRs on neutrophils andmacrophages triggering degranulation.6Systemic lupus erythematosus (SLE) Immune complex diseaseChronic IgG production to intracellular proteins.Disease symptoms are widespread and varied.– kidney damage, lung disease, skin, eye, etc.Systemic lupus erythematosus(SLE)Autoantibodies against nucleoprotein particles;– Nucleosome– Spliceosome. – Ribonucleoprotein complex.Th response to one epitope can drive auto-antibodyproduction to many epitopes in a particle.LupusOne T helperepitope canprovide help tomultipleantibodyepitopes insame particle.Potential disease cycle for SLEImmune complexes form -->– get deposited in joints, small blood vessels --->– C' activation, activation of phagocytes --->– Inflammation/damage causes more release of intracellularantigens and then– MORE immune complexes can form7T cell Mediated Autoimmune DiseasesMultiple sclerosis (MS)T cell responses to myelin basic protein (MBP).The destruction of the myelin sheath results inneurological symptoms.Multiple sclerosis (MS)The cause remains unknown, but autoimmunitypossibly triggered during an inflammatoryresponse to a viral infection is implicated. MBP has high sequence homology with measlesprotein and Hepatitis B virus protein. Antigenic mimicry?Insulin-dependent (type I)diabetes mellitus (IDDM)Selective destruction of insulin-producing β cellsin the islets of Langerhans of the pancreas.Autoantibodies and self-reactive T cells have beenfound in human patients with IDDM.Type I diabetesSpecific killing of insulin producing β islet cells8DiabetesCD8+ CTLs are thought to be responsible for theactual killing of the islet cells.Autoantibodies are present in IDDM.– However, animal models of IDDM have shown thatthese autoantibodies alone cannot cause IDDM.Experimental autoimmuneencephalomyelitis (EAE)Mouse model for multiple sclerosisInjection of normal mice or rats with MBP incomplete Freund's adjuvant can induceEAE.EAE Mouse Model for MSMBP-specific CD4+T cell clones can be isolated from mice with EAE and injection into normal animals to cause disease.9EAE Model for MSImmunodominant epitopes of MBP havebeen identified.Different MHC haplotypes have one or twoMBP peptides that are encephalitogenic,(i.e. capable of inducing disease).NOD (non-obese diabetic) miceMouse model of IDDMNOD mice spontaneously develop insulitisand "diabetes-like" disease between 2 and 4months of age.NOD mice injected with Treg cells delaydeveloping diabetes.These Treg (CD4+ CD25+) cells cansuppress by making--IL-10, TGF-β.Mouse Model of LupusF1 cross of NZ Black X NZ White mice– Mice spontaneously develop immune complex diseasesimilar to SLE. Abs to DNA, nucleoproteins.– Genetically complex heterozygous model of disease.– But used to identify lupus-associated genes e.g. Nba.2B6.Nba2 Mice as Model of LupusAutoantibody production in female vs male B6.Nba2 miceJ Immunol. 2005 Nov 1;175(9):6190-6.B6.Nba2 miceare congenic forthis lupusassociatedgene-- but DONOT developfull disease buthave genderdifferences.10Susceptibility FactorsMHCRelative Risk--- ratio of