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Immune-mediated inflammatory diseases: new concepts of pathogenesis and therapy
Abul K. Abbas, MDDepartment of Pathology
UCSF
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The “young” sciences
• Of the young sciences -- molecular genetics, neuroscience, immunology --the one that most effectively bridges basic science and clinical medicine is Immunology– Sophisticated understanding of normal and
abnormal immune responses– Development of rational therapies
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Immune-mediated diseases -- 1
• Immune-mediated inflammatory diseases develop because the normal controls on immune responses fail– Excessive reactions against foreign (microbial,
environmental) antigens– Intrinsically abnormal reactions against self
antigens• Sometimes, tissue injury is part of a
normal host response– Viral hepatitis, granulomatous diseases
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The rise and fall of the normal immune response
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Diseases caused by “exaggerated” immune responses
• Post-streptococcal GN, rheumatic fever– Not known if the fundamental problem is the
amount or type of antibody produced– Not known why sequelae develop in a minority
of infected persons
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The phenomenon of “self-tolerance”
All normal individuals “tolerate” their own antigensFailure of self-tolerance results in autoimmunity
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Susceptibilitygenes
Environmental triggers,e.g. infections
Failure of self-tolerance
(unresponsiveness to self antigens)
Activation ofself-reactivelymphocytes
Autoimmune disease
Pathogenesis of autoimmune diseases
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Insulitis in type 1 diabetes
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Insulitis: CD4 stain
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IDDM15
IDDM5
IDDM8
IDDM10
IDDM17
IDDM4
16q24
16p
Provided by J Todd & L Wicker, Cambridge University
4-1BB
Idd1
Idd3Idd10Idd18.2
Idd9.1
Idd9.3
HLA
IDDM12
IDDM2
HLA CLASS II& others?
INSULIN
CTLA-4
CD101
VAV3 IL-2
Idd18.1
Idd9.2
IL2Rα
Genes associated with type 1 diabetes
XP11
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Genetics of autoimmune diseases
• Most autoimmune diseases are complex multigenic traits (numerous associated polymorphisms)
• The hope is that defining the susceptibility genes will provide clues about pathogenesis and suggest new therapeutic targets
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Crohn’s disease: colitis
Normal Inflamed
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Crohn’s disease
Transmural inflammation, mucosal granulomas
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Genes and Crohn’s disease
• About 25% of patients with Crohn’sdisease have mutations in a gene called NOD2
• The NOD2 protein is an intracellular receptor for bacterial peptides (e.g. muramyl dipeptide) that triggers protective anti-bacterial host responses
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Commensalbacteria
NOD2
Infectioncontrolled
by host response
MutantNOD2
Persistent infection
Chronic inflammation
Normal Crohn’s disease
Postulated role of Nod2 in Crohn’s disease
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Infection and autoimmunity• Crohn’s disease: association with Nod2
mutation• In a mouse model of systemic
autoimmunity:– IBD resolves in germ-free animals– Anti-DNA antibody, autoimmune hemolytic
anemia persist in germ-free animals• Role of infection differs in different
diseases (sometimes protective -- the “hygiene hypothesis”)
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Immune-mediated diseases -- 2
• Immunological diseases tend to be chronic and intractable, because --– The initiating trigger can often not be
eliminated (self antigen, commensal microbes)– The immune system contains many built-in
amplification mechanisms whose normal function is to optimize our ability to combat infections
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Amplification loop in cell-mediated immunity
Cytokines are powerful amplifiers of immune reactions
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Targeting cytokine networks for therapy
• TNF antagonists for rheumatoid arthritis, IBD
• IL-12 antagonists (and many others) in clinical trials
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Immune-mediated diseases -- 3
• The nature of the disease is determined by the type of dominant immune response– “Th1 response”: destructive inflammation;
most autoimmune diseases– “Th2 response”: IgE-eosinophil-mediated
inflammation; allergic reactions
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Subsets of CD4+ helper T cells
Under different activation conditions,CD4+ helper T cells can differentiate into subpopulations that make different cytokines and perform different functionsSignature cytokines:TH1 cells: IFN-γTH2 cells: IL-4, IL-5
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TH1 cells are involved in immune-mediated inflammatory diseases
The cytokine responsible for all these effects is IFN-γ
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TH2 cells are involved in allergic diseases
Cytokines involved:IgE production --
IL4 Eosinophil activation --
IL-5
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Susceptibilitygenes
Environmentaltriggers(infections)
Failure of tolerance
(esp. in TH1 cells)
Activation ofself-reactivelymphocytes
Autoimmunedisease
AutoimmunitySusceptibility
genes
Environmentalexposure toallergens
TH2dominance
Activation ofspecific
lymphocytes
Allergicdisease
Allergy
Pathogenesis of immunologic diseases
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Immune-mediated inflammatory diseases
• Many of these diseases develop because normal controls in the immune system fail
• These diseases tend to be chronic and difficult to eradicate
• Phenotypic variations in the diseases reflect the dominance of different types of immune responses
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The immune system and disease: where have we been and where are we going
• The normal immune response is understood in quite precise molecular detail– Value of animal models
• The greatest challenges remaining are to understand why self-tolerance fails to give rise to autoimmune diseases– Genetic approaches, clinical trials