Immune-mediated inflammatory
  diseases: new concepts of
  pathogenesis and therapy


       Abul K. Abbas, MD
     Depart...
The “young” sciences

• Of the young sciences -- molecular
  genetics, neuroscience, immunology --
  the one that most eff...
Immune-mediated diseases -- 1
• Immune-mediated inflammatory diseases
  develop because the normal controls on
  immune re...
The rise and fall of the normal immune response
Diseases caused by “exaggerated”
          immune responses

• Post-streptococcal GN, rheumatic fever
  – Not known if the...
The phenomenon of “self-tolerance”




All normal individuals “tolerate” their own antigens
Failure of self-tolerance resu...
Pathogenesis of autoimmune diseases
  Susceptibility        Environmental triggers,
     genes                   e.g. infe...
Insulitis in type 1 diabetes
Insulitis: CD4 stain
Genes associated with type 1 diabetes
4-1BB
                                                           HLA CLASS II
   Idd...
Genetics of autoimmune diseases

• Most autoimmune diseases are complex
  multigenic traits (numerous associated
  polymor...
Crohn’s disease: colitis




Normal                 Inflamed
Crohn’s disease




Transmural inflammation, mucosal granulomas
Genes and Crohn’s disease

• About 25% of patients with Crohn’s
  disease have mutations in a gene called
 NOD2
• The NOD2...
Postulated role of Nod2 in Crohn’s disease


Commensal   Normal     Crohn’s disease
bacteria
                             ...
Infection and autoimmunity
• Crohn’s disease: association with Nod2
  mutation
• In a mouse model of systemic
  autoimmuni...
Immune-mediated diseases -- 2

• Immunological diseases tend to be
  chronic and intractable, because --
  – The initiatin...
Amplification loop in cell-mediated immunity




Cytokines are
powerful
amplifiers of
immune reactions
Targeting cytokine networks for
               therapy

• TNF antagonists for rheumatoid
  arthritis, IBD

• IL-12 antagon...
Immune-mediated diseases -- 3

• The nature of the disease is determined
  by the type of dominant immune response
  – “Th...
Subsets of CD4+ helper T cells

             Under different
             activation conditions,
             CD4+ helper ...
TH1 cells are involved in immune-mediated
             inflammatory diseases




The cytokine
responsible for
all these ef...
TH2 cells are involved in allergic diseases




                         Cytokines involved:
                          IgE...
Pathogenesis of immunologic diseases

   Autoimmunity                        Allergy
                 Environmental       ...
Immune-mediated inflammatory
            diseases
• Many of these diseases develop because
  normal controls in the immune...
The immune system and disease: where
 have we been and where are we going

• The normal immune response is understood
  in...
Upcoming SlideShare
Loading in …5
×

Immune-mediated inflammatory diseases: new concepts of ...

1,592 views
1,384 views

Published on

Published in: Health & Medicine
0 Comments
1 Like
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total views
1,592
On SlideShare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
31
Comments
0
Likes
1
Embeds 0
No embeds

No notes for slide

Immune-mediated inflammatory diseases: new concepts of ...

  1. 1. Immune-mediated inflammatory diseases: new concepts of pathogenesis and therapy Abul K. Abbas, MD Department of Pathology UCSF
  2. 2. 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
  3. 3. 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
  4. 4. The rise and fall of the normal immune response
  5. 5. 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
  6. 6. The phenomenon of “self-tolerance” All normal individuals “tolerate” their own antigens Failure of self-tolerance results in autoimmunity
  7. 7. Pathogenesis of autoimmune diseases Susceptibility Environmental triggers, genes e.g. infections Failure of Activation of self-tolerance self-reactive (unresponsiveness lymphocytes to self antigens) Autoimmune disease
  8. 8. Insulitis in type 1 diabetes
  9. 9. Insulitis: CD4 stain
  10. 10. Genes associated with type 1 diabetes 4-1BB HLA CLASS II Idd9.3 VAV3 IL-2 & others? Idd9.2 HLA Idd1 Idd9.1 Idd18.1 IDDM15 Idd18.2 Idd10 CTLA-4 Idd3 IDDM5 IDDM8 IDDM12 CD101 IL2Rα INSULIN IDDM2 IDDM10 XP11 16p IDDM4 16q24 IDDM17 Provided by J Todd & L Wicker, Cambridge University
  11. 11. 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
  12. 12. Crohn’s disease: colitis Normal Inflamed
  13. 13. Crohn’s disease Transmural inflammation, mucosal granulomas
  14. 14. Genes and Crohn’s disease • About 25% of patients with Crohn’s disease 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
  15. 15. Postulated role of Nod2 in Crohn’s disease Commensal Normal Crohn’s disease bacteria Mutant NOD2 NOD2 Persistent Infection infection controlled by host response Chronic inflammation
  16. 16. 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”)
  17. 17. 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
  18. 18. Amplification loop in cell-mediated immunity Cytokines are powerful amplifiers of immune reactions
  19. 19. Targeting cytokine networks for therapy • TNF antagonists for rheumatoid arthritis, IBD • IL-12 antagonists (and many others) in clinical trials
  20. 20. 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
  21. 21. 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 functions Signature cytokines: TH1 cells: IFN-γ TH2 cells: IL-4, IL-5
  22. 22. TH1 cells are involved in immune-mediated inflammatory diseases The cytokine responsible for all these effects is IFN-γ
  23. 23. TH2 cells are involved in allergic diseases Cytokines involved: IgE production -- IL4 Eosinophil activation -- IL-5
  24. 24. Pathogenesis of immunologic diseases Autoimmunity Allergy Environmental Environmental Susceptibility Susceptibility triggers exposure to genes genes (infections) allergens Failure of Activation of Activation of tolerance TH 2 self-reactive specific (esp. in TH1 dominance lymphocytes lymphocytes cells) Autoimmune Allergic disease disease
  25. 25. 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
  26. 26. 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

×