1. Lecture outline Types of hypersensitivity reactions
Immediate hypersensitivity, allergy
Antibody-mediated diseases
T cell-mediated diseases
Therapeutic approaches

2. Immunological (hypersensitivity) diseases
Diseases caused by aberrant (excessive or uncontrolled) immune reactions
Reactions against self antigens (autoimmunity)
Uncontrolled or excessive reactions against foreign antigens
Underlying problem may be failure of self-tolerance and control mechanisms
The nature of the disease is determined by the type of immune response
Diseases are classified based on immune mechanisms: useful for understanding pathogenesis, but many diseases involve multiple mechanisms

3. Types of hypersensitivity disease
Type of hyper-
sensitivity
Pathogenic immune
response
Mechanism of
tissue injury
Immediate hyper-
sensitivity (Type I)
IgE antibody,
mast cells
Mast cell mediators
Phagocytosis
Complement
Interference with
cell functions
IgM and IgG antibodies
against cell and matrix
antigens
Antibody mediated
(Type II)
Complexes of circulating
antigens and IgM or
IgG antibodies
Complement and Fc
receptor mediated
inflammation
Immune complex
mediated (Type III)
Cytokine-mediated inflammation
Killing by CTLs
T cell mediated
(Type IV)
CD4 and CD8 T cells

4. Immediate hypersensitivity reaction

5. Stages of immediate hypersensitivity reactions

6. Sequence of events in immediate hypersensitivity

7. Actions of mast cell mediators
Mast cell products are responsible for the manifestations of
immediate hypersensitivity

8. Clinical manifestations of immediate hypersensitivity

9. Treatment of immediate hypersensitivity disorders

10. Genetic susceptibility for immediate hypersensitivity
Allergic diseases run in families
Different members of the same family may show different manifestations of immediate hypersensitivity (“atopy”)
Multiple susceptibility genes have been identified by gene mapping and family studies
Genes may influence TH2 responses, IgE production, mast cell activation, end-organ sensitivity
Susceptibility loci identified include: HLA (immune responsiveness); cytokine gene cluster; others

11. How antibodies deposit in tissues
Antibody is
specific for
tissue antigen
(typically self):
disease is
target tissue
Antibody reacts
with circulating
antigen (self
or foreign), and
complexes tend
to deposit in
small vessels; not
specific for
any tissue

12. How antibodies cause disease -- 1
Neutrophils (and monocytes) are recruited by complement
products (generated by the classical pathway) and binding to Fc
tails of deposited antibodies, and are activated.
Leukocyte recruitment and activation are part of inflammation.

13. Experimental models of immune complex diseases
Serum sickness
Systemic immunization with large dose of protein antigen --> circulating immune complexes --> complexes deposit in vessels and cause inflammation (Fc receptor and complement-mediated)
Arthritis, vasculitis, glomerulonephritis
Arthus reaction
Subcutaneous administration of antigen in previously immunized individual --> formation and deposition of local immune complexes
Cutaneous vasculitis

14. Immune complex-mediated glomerulonephritis

15. Anti-basement membrane antibody- mediated glomerulonephritis

16. How antibodies cause disease -- 2
Antibody and/or complement (C3b) are deposited on cell and
are recognized by receptors for Fc or C3b on phagocytes -->
coated (opsonized) cell is ingested and destroyed.
Basis of autoantibody-mediated depletion of RBCs, platelets

17. How antibodies cause disease -- 3

18. Causes of antibody-mediated diseases
Autoimmunity (production of autoantibodies)
May be due to failure of self-tolerance in autoreactive B cells or helper T cells
Antibody responses to foreign antigens
Antibodies against hepatitis B form immune complexes --> vasculitis (polyarteritis nodosa)
Post-streptococcal glomerulonephritis: immune complexes of Strep antigen + anti-Strep antibodies; formed in circulation or GBM
Not known why immune complex diseases develop in rare individuals after common infections

19. How T cells injure tissues -- 1
CD4+ T cells respond to self (or microbial) antigens, produce cytokines that recruit and activate macrophages and neutrophils, and the products of these leukocytes damage tissues.
Recall that the same reaction destroys phagocytosed microbes (cell-mediated immunity, one arm of host defense)

20. Delayed type hypersensitivity (DTH) reaction
Detectable reaction to an antigen in a sensitized (previously exposed) individual
Caused mainly by CD4+ T cells  cytokine secretion  inflammation, macrophage activation

21. Morphology of a delayed type hypersensitivity
(DTH) reaction
Classically attributed to Th1 response; may include Th17.

22. How T cells injure tissues -- 2
Cytotoxic T lymphocytes (CTLs) react against antigens
in host tissues and kill (“lyse”) the host cells.

23. Causes of T cell-mediated hypersensitivity diseases
Autoimmunity
Type 1 diabetes, multiple sclerosis, rheumatoid arthritis, psoriasis
Reaction to microbes and other foreign antigens
Contact sensitivity (DTH) to chemicals (poison ivy)
Tuberculosis (granulomatous inflammation in response to a persistent microbe: chronic DTH)
Crohn’s disease (excessive Th1 and Th17 responses to gut commensals?)
Viral hepatitis (CTLs kill virus-infected hepatocytes); not considered an example of “hypersensitivity”

24. Immune-mediated inflammatory diseases
Chronic diseases in which inflammation is a prominent component and the immune system reacts excessively against one or more tissues
Major role of CD4+ T cells and cytokines; antibodies may contribute to disease
Same therapies work in many of these diseases
These diseases develop because the normal controls on immune responses fail; typically due to autoimmunity but may be excessive reactions to microbes
MS, type 1 diabetes, RA: autoimmunity
Crohn’s: reaction against gut microbes?

25. Chronicity of immune-mediated inflammatory diseases
Many of these hypersensitivity diseases are chronic and even self-perpetuating because:
The initiating stimuli cannot be removed (self or environmental antigens, persistent microbes)
The immune response tends to amplify itself (normally, enables few antigen-specific lymphocytes to deal with infections)

26. Amplification loop in DTH reactions
Cytokines are
powerful
amplifiers of
immune reactions

27. Therapy of immune diseases: the current way
Block the production or counteract the actions of effector molecules that cause tissue injury
Anti-inflammatory drugs, e.g. steroids
Block T cell activation (immunosuppressive drugs, e.g. cyclosporine)
Deplete pathogenic antibodies (plasmapheresis), B or T lymphocytes (depleting antibodies)
Empirical
Desensitization for allergy
Intravenous IgG (IVIg): engages inhibitory FcR on B cells?

28. Therapy of immune disorders: rational approaches target lymphocyte activation and subsequent inflammation
CTLA-4.Ig
(block costimulation)
Inhibitors of calcineurin, various kinases
(inhibit signaling)
CD28
IL-2
TCR
APC
Anti-IL-2R
(block cytokine receptor)
T cell
IL-12, IL-23
(p40)
TNF, IL-1,
IL-6R
antagonists
(block cytokines)
TNF, IL-1,
IL-6
IL-17A
Anti-IL-17A
Anti-p40
Anti-integrin antibodies
(block adhesion)
Inflammation

29. Molecularly targeted therapies for immunological diseases: the rational approach
Target the molecular basis of lymphocyte activation and effector functions: rationally designed therapies
Based on understanding of lymphocyte biology
Risks -- reactivation of infections
Induce antigen-specific immunological tolerance: requires identification of target antigens
Being tried in MS, type 1 diabetes (in which the major autoantigens are known)