MOD #95
Wed 5/14 1pm
Michael Carletti
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Mechanisms of Disease
Diseases of Immunity
Stephen L. Putthoff, D.O., FCAP
Assigned material for this block
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1. Robbins Pathologic Basis of Disease, 6th Ed., Chapter 7, Diseases of
Immunity
2. McKenna, et al, Handbook of Clinical Pathology, 2nd. Ed. ( correlated to
Robbins)
Chapter 29, Autoimmune Diseases
Chapter 30, Immunodeficiency Diseases
General features of the Immune System – review material*
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Cells of the Immune System
Cytokines: Messenger Molecules of the Immune System
Structure and Function of Histocompatibility Antigens
Disorders of the Immune System** organization (chpt 7) [ from pg 195 and
on ]
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Mechanisms of Immunologic Tissue Injury* (Hypersensitivity reactions)
transplant rejection - hyperacute, acute, chronic
Autoimmune diseases* - central vs peripheral tolerance of own self
antigen
Immunologic deficiency syndromes – impairment of immunologic pathway
amyloidosis – seen in wide variety of chronic inflammatory states
Hypersensitivity reactions** ( know prototypical examples of each )
 Table 7-2**, pg. 196
 Type I - anaphylactic type ; most common (1)
 Type II - cytotoxic type
 Type III - Immune complex disease
 Type IV – cell mediated (delayed) hypersensitivity ; most common (2)
HLA and disease association(s)* Table 7-1, pg. 195*
Can be grouped into three categories*
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Inflammatory diseases
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Inherited disorders of metabolism
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Autoimmune diseases (criteria must be met, best examples systemic
lupus erythematosus and autoimmune hemolytic anemia
Role of HLA class II molecules
HLA B27 is correlated to ankylosing spondylitis involves lower lumbar spine
where there is chronic inflammatory reactions can progress to other
musculoskeletal structures
Type I hypersensitivity (anaphylactic type)
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Can be defined as a rapidly developing immunologic reaction occurring
within minutes after the combination of an antigen with antibody bound to
mast cells or basophils in individuals previously sensitized to the antigen
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Fig. 7-9, pg. 197* of bronchial epithelium (airway) – fixation of IgG
antibodies to mast cells, the antibody is really IgE and is fixed by the Fc
portion to the mast cell; when other antigens attach to the Fab portion they
degranulate the mast cell
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May be a local or systemic phenomenon – systemic is more important due
to fear of shock due to lack of profusion of vital organs and increased
vascular permability after a reaction to an antigen to which you have been
exposed to previously
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The role of basophils (circulating in white blood cells) and mast cells (
found in tissue and is fixed version of basophils)
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In humans, type I reactions are mediated by IgE antibodies – Fig 7.10 pg
198
Primary (histamine and proteases) and secondary (leukotrienes and
prostaglandins) mediators – to treat allergies they give antihistamines
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Summary of the action of mast cell mediators in type I hypersensitivity –
Table 7-3 pg 199
Cellular infiltration
Vasoactive
Smooth muscle spasm
Two major reactions in this degranulation is tissue edema due to vascular
dilatation and loss of fluid into interstitial space; with this you hear wheezing
with a stethoscope
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Type II hypersensitivity (cytotoxic type) [ damage is done on site]
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Mediated by antibodies directed toward antigens present on the surface of
cells or other tissue components
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Complement –dependent reactions : to produce injury antibody-antigen
complex activates the complement system; by itself it is not pathogenic,
however: example is of autoimmune hemolytic anemia – target cell is RBC
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Antibody-dependent cell mediated cytotoxicity : example is ADCC
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Antibody mediated cellular dysfunction : example myasthenia gravis
affecting motor end plate in which there are antibodies against
acetylcholine recptors and block them; end up with lack of ability of muscle
to contract; early manifestation is droopy eyelids
Type III hypersensitivity (immune complex mediated) – Table 7-5 pg 201
[ damage depends on where things are deposited ]
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Old term = serum sickness
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is induced by antigen-antibody complexes that produce tissue damage as
a result of their capacity to activate the complement system
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Two types of antigens
exogenous* - pathogens and some drugs and injected substances (due to
their contaminants that cause immunologic reactions); will endocarditis of drug
abusers
endogenous** - most important is systemic lupus; another is rheumatoid
arthritis which the antigen is an antibody
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Systemic immune complex dz – 3 phases
- Formation of Ag-Aby complexes in the circulation
- Deposition of the immune complexes in various tissues, thus
- Initiation of an inflammatory reaction in dispersed sites throughout the
body
platelet aggregation – any disorder of platelets; most studied by bleeding time
most often ends in necrosis
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look over complement pathway – MAC the inflammatory complement mediators
Type III hypersensitivity (immune complex mediated) – systemic, usually
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The ultimate result is vascular injury
Blood vessels = vasculitis
Glomeruli = glomerulonephritis, but doesn’t always mean inflammatory or
infectious
Joint surfaces = arthritis, mostly rheumatoid in which an IgG is directed
against IgM
called leukocytoclastic vascultits indicating multiple inflammatory cells, necrosis
and don’t know what the inciting agent is, until it is diagnosed
Type III hypersensitivity (immune complex mediated) - local
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Arthus reaction – [def] a local area of tissue necrosis resulting from acute
immune complex vasculitis, typically in the skin ; not used anymore – they
use purified protein derivative (PPD)
Type IV hypersensitivity (cell mediated not so much humoral, therefore T
cell)**
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The cell mediated type of hypersensitivity is initiated by specifically
sensitized T lymphocytes. It includes the classic delayed-type
hypersensitivity reactions initiated by CD4 T cells and direct cell
cytotoxicity mediated by CD8 T cells. It is the principal pattern of
immunologic response not only to a variety of intracelluar microbiologic
agents, particularly Mycobacterium tuberculosis, but also to many viruses,
fungi, protozoa and parasites. So-called contact skin sensitivity to
chemical agents and graft rejection are other instances of cell-mediated
reactions.
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Delayed-type (classic example) – tuberculin reaction ; not used anymore –
they use purified protein derivative (PPD)
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granulomatous inflammation is often characteristic of Type IV
hypersensitivity- differs from lymphoid follicle which is composed of B
lymphocytes in the center and T lymphocytes surrounding – found in TB,
sarcoidosis, fungal diseases
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T cell-mediated cytotoxicity
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CTLs (cytotoxic T lymphocytes)
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A variety of roles
antigen presenting cell is normally a macrophage
transplant rejection
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Appears to involve several of the hypersensitivity reactions
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Rejection is a complex process in which both cell mediated immunity and
circulating antibodies play a role
T cell mediated reactions
Antibody mediated reactions
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morphology
- hyperacute
- acute
- chronic
note schematics and photomicrographs pg 208,209
Autoimmune diseases
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[def] pathologic immunity (3 criteria)
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Table 7-6** pg 211 look at single organ / single cell type / systemic ones
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The autoimmune diseases form a spectrum
- autoantibodies specifically directed against B cells in the pancreatic islets (ID
DMI)
- antibodies directed against components of glomerular and alveolar septal
basement membranes cause injury and disease in those specific organs)
- a diversity of antibodies directed against DNA, platelets, red cells and
protein-phospholipids complexes resulting in lesions ubiquitous throughout the
body (SLE)
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Immunologic tolerance ( know how they go wrong )
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- Central tolerance
- Peripheral tolerance
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Mechanisms of autoimmune diseases
-it is clear that there are a number of ways by which tolerance can be
bypassed, thus terminating a previously unresponsive state to autoantigens
pp. 214 – 215, esp. genetic factors
Systemic lupus erythematosus ( SLE )
[wolf like facies around eyes and cheeks]
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The classic prototype of the multisystem disease of autoimmune origin,
characterized by a bewildering array of autoantibodies, particularly
antinuclear antibodies (ANAs)
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Acute or insidious in its onset, it is a chronic, remitting and relapsing, often
febrile illness characterized principally by injury to the skin, joints, kidney
and serosal membranes. However, virtually any and possibly every other
organ in the body may also be affected
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Table 7-7, pg. 217* clinical manifestations: fluid from cavities lined by
mesothelial cells causing plural effusions, pericarditis (virtually every body
cavity)
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Prevalence
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gender predilection – more common in women
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ethnic predilection
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Etiology and pathogenesis
-ANAs can be grouped into (4) categories*
-Know the patterns of nuclear immunofluorescence
-Which antibodies (2) are virtually diagnostic of SLE? (anti-DNA, anti-Sm)
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See Table 7-8**pg 218 and group by antibody system know the ones in
boxes ; these are just clinical correlations so don’t just do an ANA unless
you suspect the disease, and don’t just diagnose based on the ANA
pattern
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genetic factors
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nongenetic factors
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immunologic factors
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Morphology
-Table 7-9, pg. 220*
-Summary of disease, pg. 220*
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Clinical course (what are the most common causes of death due to SLE?)
Chronic discoid lupus erythematosus
Subacute cutaneous LE
Drug-induced LE