Disorders in Immunity
Hypersensitivies, Autoimmune Disease, Immune Deficiency, Graft Rejection
The student is expected to know:
1.
Terms: allergans, hypersensitivity, autoimmune disease, immunodeficiency, graft rejection
2.
Two opposite sides of immune response (over-reaction and under-reaction)
3.
Type I: IgE mediated Immediate or delayed Hypersensititivy; mechanism and components,
examples
4.
Type II: Cytotoxic autoimmunity: mechanism and components, examples
5.
Type III: Immune Complex: mechanism and components, examples
6.
Type IV: Delayed type hypersensitivity; mechanism and components, examples
7.
Autoimmune Disease; definition; possible causes, cell types, examples
8.
Immunodeficiencies; definition, primary and secondary types and cells, outcomes
9.
Transplant – rejection graft, types, outcome
10.
Cancer – surveillance, cell types
I.
Introduction
A.
Abnormal immune response
1.
may be detrimental to the host, not beneficial
2.
may be overactivity or underactivity of immune response
B.
Terms
1.
Hypersensitivity: A pathologic change (manifested by inflammation) in the
host as a result of a response to an antigen; may occur immediately after
exposure to antigen. Types I – IV
2.
Allergen: antigen induces allergic immune response in sensitive individuals.
3.
Autoimmune – autoantigens that are recognized as foreign and attacked
4.
Tissue Graft – foreign tissue that is recognized as foreign and attacked
5.
Immunodeficiency – abnormality in presence of or function of some part of
the immune system, results in reduced or absent immune response
II.
Type I Hypersensitivity Reactions: Anaphylaxis (Immediate Hypersensitivity), Atopy
A.
Terms
1.
Anaphylaxis – immediate, acute, systemic immune response, may be life
threatening
2.
Atopy – chronic local allergy; asthma and hay fever
B.
Immediate Hypersensitivity
1.
IgE and mast cell mediated – Anaphylactic (against protection, harmful)
a.
Terms for Type I
i.
localized – local immune response; hay fever, asthma
ii.
systemic – throughout the body, soluble mediators
b.
mechanism – very rapid
i.
Sensitizing dose of allergen stimulates antibody (IgE)
response. Pollen, venom, penicillin, albumin.
ii.
Illiciting (provocative) dose – second exposure to allergen
induces rapid IgE response (memory).
iii.
IgE binds to FC receptors on mast cells and basophils in
tissues at site, and to specific allergen at site
iv.
Mast cells release chemical mediators; histamine, serotonin,
heparin, bradykinin, prostaglandin, leukotrienes, platelet
activating factor, etc.
Histamine – fast acting, constriction of bronchial smooth muscle,
vasodilation arterioles, edema, hypotension, shock, cardiac failure
d.
Serotonin – increases vascular permeability, capillary dilation,
smooth muscle contraction, hypotenion, shock
e.
Leukotriene – slow, gradual contraction of smooth muscle, mucous
secretion, activates PMNs, airway constriction
f.
Platelet Activating Factor – platelet aggregation and lysis, similar to
histamine, pulmonary edema, hypotension, chemotactic
2.
Symptoms – within minutes; can be fatal - Capillary, blood vessel dilation,
smooth muscle contraction, tachycardia, difficulty breathing, mucous
release, fluid loss into tissues causes hypotension, swelling, itching (edema,
erythema), shock, death
3.
Treatment must be immediate
a.
Epinephrine & antihistamine – reverses histamine, serotonin effect
b.
Both lead to smooth muscle dilation, makes breathing easier
c.
Cortisone – anti-inflammatory; inhibits leukocyte activity
Atopy - IgE mediated delayed hypersensitivity
1.
IgE and eosinophils recruited from bone marrow by T helper cells (takes
longer) cause chronic response to allergen (may be genetic)
2.
Chronic disease – dermatitis, inflammation to food, other allergans
a.
Diseases
i.
Asthma
b.
severe bronchoconstriction - impaired breathing
c.
Chronic inflammation and thick mucous plug
d.
Imbalance in nervous control of respiratory smooth
muscle
e.
Allergans cause cytokine overproduction –
cockroaches, mold
f.
10 million and rising; range from annoyance to fatal
ii
Hay fever or food allergy
a.
eczema or more systemic inflammatory response,
mild to fairly severe atopy
b.
T cells turn on IgE and not IgM or IgG in response
to food, pollen, other allergans
c.
Drug allergies may also cause atopic reactions
c.
C.
III.
Type II Hypersensitivity: Antibody dependent cytotoxicity
A.
Mediated by IgG and IgM and complement
B.
Lysis of cells by complement/Antibody binding and formation of MAC
C.
Mechanism
1.
Repeated or single exposure to antigen activates complement pathway
2.
Can elicit production of cross reactive antibodies to self antigen
3.
Antibodies bind to antigen and fix complement, attract neutrophils, cytotoxic
to tissues
4.
Symptoms
a.
fever, rash, swelling lymph nodes, ankles and face
b.
Internal damage – kidney dysfunction, arthritis, cardiac and vascular
damage due to antigen-antibody complexes.
5.
Causes
a.
Blood transfusions - anti-RBC fixes complement – causes hemolytic
anemia, can be fatal, may need immediate transfusion
2
b.
c.
c.
d.
Blood antigens - ABO blood group, Rh, Kell, Duffy, MN. (Also
antigens on neutrophils, leukocytes).
Rh incompatibility
i.
first pregnancy - Rh negative mother is sensitized during
delivery with an Rh positive neonate
ii.
second pregnancy, fetal RBCs leak across the placenta and
illicit a secondary immune response in the mother.
iii.
Maternal antibodies to Rh antigen on fetal RBCs cross
placenta, cause complement mediated lysis of RBCs
iv.
Hemolytic disease of newborn, erythroblastosis fetalis
v.
Infant symptoms – circulatory blasts, jaundice, anemia,
hepatosplenomegaly, blue color - lack of hemoglobin
Drugs may cause the production of antibodies that cross-react with
the RBC and cause anti-RBC abs that fix complement.
Autoimmunity (see below)
ii.
Rheumatic fever
(1)
Antibody to Streptococcal M protein cross-reacts
with the heart muscle, anti-M attacks heart
(2)
Immune complexes form, lodge in kidneys, joints
ii
Goodpastures nephritis and Myasthenia gravis (autoimmune)
IV.
Type III hypersensitivities: Immune Complex Reactions
A.
Involves the production of IgG and IgM, complement, PMNs (neutrophils)
B.
Repeated exposure of antigen
C.
Immune complexes (Ag/Ab/Complement) are deposited in the tissues
D.
Mechanism of Immune Complex Disease
1.
Large amounts immune complexes can not be cleared by phagocytes
2.
Complexes are deposited in basement membranes epithelial tissues
3.
PMNs release lysosomal granules that digest tissue and cause inflammatory
conditions, vasular damage and organ malfunction
E.
Types of Immune complex Diseases
a.
Arthus reaction (serum sickness)
i.
local immune complexes in tissues due to injection of
antigen
ii
Drug induced systemic sickness (can be vaccine if xeno)
b
Systemic lupus erythematosus (SLE) – autoimmune disease
i.
Antibodies against numerous formed elements, tissues
iii.
Immune complexes lodge in numerous organs, kidney
c.
Rheumatoid Arthritis (RA) – autoimmune disease
i.
Antibodies against autoantigens
ii.
Joints are target of immune complex deposition
V.
Type IV Hypersensitivity – Delayed Type Hypersensitivity (DTH)
A.
Mediated by DTH T cell, langerhaans, macrophages, cytokines, no antibodies
B.
Slower than Types I, II, and III – usually several days.
C.
Lack of response is no exposure or cellular immunity deficiency.
D.
Types of DTH (all are delayed reaction)
1.
Contact hypersensitivity - excema reaction site of allergen contact
2.
Skin test (TST) - cutaneous reaction to 2nd exposure to TB, max 2 days
3.
Granulomatous – normal cellular response (macrophages, T cells, epithelial)
to a chronic persistent disease or intracellular antigen
3
E.
F.
DTH granulomatous reaction is seen in several infectious diseases
1.
Mycobacterium tuberculosis (TB), Mycobacterium leprae (leprosy)
2.
Systemic fungi, intracellular organisms
3.
Sarcoidosis
DTH in contact dermatitis (eczematous reactions)
1.
Antigens are plants, poison ivy, metals (nickle), drugs and rubber
2.
Requires a sensitizing and provocative dose introduced into skin
3.
lymphocyte, langerhaans (macrophages) react, release cytokines
4.
Damage to epidermal cells causes itching and inflammation
VI.
Autoimmune disease – autoantibodies, T cells mount immune response to self antigens
A.
Loss of tolerance to self antigens (5% US) - genetic susceptibility, females more
B.
Mediators (Type II and Type III)
1. Activation of T helper cells that recognize self as foreign, direct antibodies
2. T cell response is turned by innate and not turned off
3. Involves immune complexes and cytopathology
C
Causes hypothesized (probably combination and genetic)
1.
Microbial infection – molecular mimicry (cross-reactive antigens)
2.
forbidden clones – escape education and removal
3.
T-suppressor cell dysfunction – don’t turn off when appropriate
4.
sequestered antigen becomes exposed (neural, eye)
D
Examples
1.
Systemic Lupus Erythematosus (SLE)
a.
autoantibodies to many autoantigens throughout the body
b.
IC deposition many sites (target kidney), Anti-nuclear ab
2.
Rheumatoid arthritis
a.
progressive debilitating joint disease
b.
synovial fluid, joints have immune complexes and complement
3.
Diabetes mellitis
a.
Endocrine gland autoimmunity
b.
Type 1 – insulin dependent; lytic autoantibody to islets of
langerhaans of pancreas reduces insulin production
c.
Type 2 – non-insulin dependent; autoantibodies bind insulin receptor
preventing insulin from binding therefore not usable
4.
Myastenia gravis
a.
Neuromuscular autoimmune, progressive muscle weakness
b.
Autoantibody to acetylcholine receptor, acetylcholine can’t bind
5.
Multiple sclerosis – T cells and chronic inflammation destroy myelin sheath
VII.
Organ Transplantation
A.
Overview Host rejection of Graft
1. T helper cells recognize APC processed non self and T cytotoxic recognize
different Class I as foreign
2. T helper/cytotoxic - immune response, release lymphokines, destroy graft tissue,
antibodies bind to foreign tissue and fix complement
B.
Overview of Graft rejection of Host
1.
Usually in Bone marrow transplants but can be in any
2.
Systemic and toxic response and high percentage of death
C.
Terms
1.
autograft – tissue from one part of same body grafted to other site
2.
Isograft – syngeneic (identical twin), not rejected
4
3.
4.
Allografts – most common, two different humans, often rejected
Xenograft – different species, usually temporary, future direction
VIII.
Immunodeficiency Disease – subnormal immune response
A.
Abnormality in the immune system either specific or nonspecific
B.
Primary (genetic at birth) or Secondary (acquired natural, artificial agents)
C.
Cell types affected: B cells, T cells, PMNs, macrophages, complement, other
D.
B lymphocytes - Can be defects in the formation or function
1. a (hypo) gammaglobulinemia (Primary and Hereditary)
a.
B cell decreased surface Immunoglobulin, normal T cell
b
Plasma cells decreased, all classes of Ig decreased or.absent
c.
repeated virulent bacterial and viral infections result
2.
Acquired – suppressor T cells prevent B cells to form plasma cells
E.
T lymphocytes
1.
Broad spectrum since T cells play a central role in IR
2.
DiGeorge syndrome
i.
congenital absence thymus gland, deficient T and B cell
ii
numerous abnormalities in various body systems
F.
Combined deficiencies - T and B cell deficiencies (life-threatening)
1.
Severe combined immunodeficiencies (SCIDs)
a.
life threatening genetic defect
b.
all lymphocyte numbers are abnormal (requires protective isolation)
2.
Adenosine deaminase deficiency (ADA)
a.
ADA enzyme builds up in lymphocytes and kills them
b.
X linked, life threatening, requires protective isolation
G.
Secondary deficiencies
1.
Four general agents cause this
a.
infection
b.
organic disease
c.
chemotherapy
d.
radiation
2
Acquired Immunodeficiency Syndrome (AIDS)
a.
viral infection of CD4 T helper cells, kills them
b.
life threatening
3.
Cancer lymphoid tissue/bone marrow - immunosuppression may save life but
host open to infection or damage organs, bone marrow
IX
Cancer
A.
Role of the Immune System in Cancer
1.
Immune surveillance – recognition and killing of tumor cells when they first
begin to grow
2.
Cells recognize abnormal, foreign surface markers (presented in context with
MHC for CTL or alone for NK cells) and destroy the tumor cells (binding,
release of lymphotoxin, destroys cell membrane)
3.
Cells – Natural Killer cell, Cytotoxic T cell (CD8)
5