03/13a Hypersensitivity III & IV, Granulomas

Question 1

What is autoimmune thrombocytopenic purpura? Describe its symptoms, mechanisms, and treatments

Answer 1

Caused by IgG against platelet membrane glycoproteins
Leads to opsonization and phagocytosis by splenic macrophages
Symptoms - thrombocytopenia, petechiae
Treatment - steroids, immunosuppression, splenectomy

Question 2

What is pemphigus vulgaris? Describe its symptoms and mechanisms

Answer 2

Caused by antibodies against desmosome proteins of keratinocytes
Leads to loss of attachment of epidermal keratinocytes
Symptoms - blisters, mucocutaneous erosions

Question 3

What is Goodpasture’s Syndrome? Describe its mechanisms and symptoms

Answer 3

Caused by IgG against type IV collagen, which react with the capillary basement membrane of the kidney and lung
Stimulates inflammation
Leads to renal failure due to glomerulonephritis and pulmonary hemorrhage

Question 4

What is a Type III hypersensitivity?

Answer 4

An immune complex-mediated disease

Question 5

What causes the clinical manifestations of Type III hypersensitivity reactions?

Answer 5

Immune complexes, composed of antibodies bound to self or foreign antigen, which deposit in tissues activate complement
Symptoms reflect the site of immune complex deposition, not the cellular source of the antigen
Affects multiple organs and tissues, particularly the kidneys and joints

Question 6

What are two important physical characteristics of pathogenic immune complexes? Why are they important?

Answer 6

Small size - small complexes penetrate tissue better and persist in circulation longer (avoid phagocytosis better) than large ones
Positive charge - bind tightly to negatively charged components of the basement membranes of blood vessels and kidneys

Question 7

Why are neutrophils attracted by immune complexes? Why is this significant?

Answer 7

Activation of complement by immune complexes leads to the release of C5a, a chemoattractant
Attracts neutrophils, which can cause tissue damage

Question 8

What are six examples of immune complex diseases?

Answer 8

Arthrus reaction
Serum sickness
Systemic lupus erythematosus
Polyarteritis nodosa
Poststreptococcal glomerulonephritis
Farmer's Lung

Question 9

What is the Arthrus Reaction? Describe its mechanisms and effects

Answer 9

A response to a subcutaneous injection of antigen into a previously immunized host
Circulating antibodies bind rapidly to the antigen
Complexes are deposited in the walls of small arteries, complement is activated, neutrophils are recruited
Symptoms - local cutaneous vasculitis, possible tissue necrosis

Question 10

What is serum sickness? Describe its mechanisms

Answer 10

A response to an intravenous injection of foreign protein, serums, or haptens (due primarily to drug exposure)
Antibody response occurs after about 14 days
Immune complexes form in circulation and deposit in the walls of blood vessels, stimulating inflammation and causing systemic symptoms

Question 11

What are the symptoms of serum sickness?

Answer 11

Rash
Joint pain
Fever
Lymphadenopathy
Glomerulonephritis
Proteinuria

Question 12

What is SLE?

Answer 12

Systemic lupus erythematosus - the Prototypic Immune Complex-Mediated Disease!

Question 13

What causes lupus?

Answer 13

Autoantibodies, particularly anti-DNA antibodies

Immune complexes cause vasculitis involving small arteries throughout the body

Question 14

What are the symptoms of lupus?

Answer 14

Rashes ("butterfly" pattern on the face)
Arthritis
Glomerulonephritis ("Lupus Nephritis")
Hemolytic anemia
Thrombocytopenia
Pericarditis, myocarditis, endocarditis
Photosensitivity
CNS involvement

Question 15

What is the diagnostic test for SLE?

Answer 15

Test for antinuclear antibodies, particularly antibodies against double-stranded native DNA

Question 16

What types of genetic characteristics can lead to SLE?

Answer 16

Being female
Deficiencies in complement proteins, especially C1q, C2, and C4
HLA-DR3 allele

Question 17

What is polyarteritis nodosa? Describe its mechanisms and symptoms

Answer 17

Immune complex deposition in small and medium arteries, resulting in ischemic damage
Affected organs can include the skin, heart, kidneys, and nervous system
Generalized symptoms - fever, fatigue, weakness
Skin - rashes, swelling, ulcers, lumps

Question 18

With what other disease is polyarteritis nodosa associated?

Answer 18

Active hepatitis B infection (30% of patients)

Question 19

What is poststreptococcal glomerulonephritis? Describe its mechanisms and symptoms

Answer 19

Lodging of immune complexes in the glomerular basement membrane, as a result of streptococcal skin infection
Complexes also activate complement - causes destruction of the basement membrane
Symptoms - hematuria, oliguria, edema, hypertension, heavy proteinuria, nephritic syndrome

Question 20

What is Farmer’s Lung? Describe its mechanisms

Answer 20

Hypersensitivity pneumonitis induced by the inhalation of biologic dusts
Sensitization to dusts leads to production of IgG, which binds to antigens upon subsequent exposure
Immune complexes deposit in the alveoli, leading to complement activation, inflammation, cell damage, and fibrosis

Question 21

What are the three types of Farmer’s Lung? Describe their symptoms and differences?

Answer 21

1) Acute - develops after large exposure to antigen and causes fever, chills, cough, dyspnea, chest tightness, possible acute respiratory failure
2) Subacute - less antigen over a longer period and causes dough, dyspnea, anorexia, and weight loss
3) Chronic - prolonged and continuous exposure to antigen and can cause irreversible lung damage, sever dyspnea

Question 22

What is a type IV hypersensitivity reaction?

Answer 22

Cell-mediated hypersensitivity - does NOT involve antibodies

Question 23

What is delayed-type hypersensitivity? What are the steps in the development of such a reaction?

Answer 23

Model of type IV hypersensitivity
Step 1 - sensitization by immunization, infection, or contact with chemical or environmental antigens
Step 2 - wait about 2 weeks for adaptive immunity to develop
Step 3 - elicitation by subsequent exposure to the same antigen alone, which activates local memory and effector T cells, which make cytokines

Question 24

What is the classic clinical application of the delayed-type hypersensitivity reaction?

Answer 24

Tuberculin purified protein derivative (PPD) test

Tests for T cells that have been activated by PPD antigens

Question 25

What is contact hypersensitivity?

Answer 25

Similar to DTH, except that antigens do not need to be injected, but only need to make contact with the skin
Usually involves small molecules (synthetic compounds, complex-forming heavy metals, natural plant compounds) working as haptens

Question 26

What causes poison oak rashes?

Answer 26

Pentadecacatechol in poison oak leaves contacts your skin and modifies your self proteins
This stimulates a Th1 cell response and the recruitment of macrophages, which destroy connections between keratinocytes
This causes edema and blisters

Question 27

What causes poison ivy blisters?

Answer 27

Similar to the mechanism of poison oak, but CD8 cells can also be activated by the chemical hapten penetrating into the cytoplasm of cells and being presenting by MHC class I
This activates CD8 cytotoxic T cells, which lyse cells displaying pentadecacatechol and causes contact dermatitis

Question 28

What is a cell-mediated hypersensitivity response?

Answer 28

An injurious cytokine-mediated inflammatory reaction resulting from the activation of T cells, particularly CD4 T cells
Usually causes chronic inflammation

Question 29

What cytokines are involved in cell-mediated hypersensitivity reactions? What are their effects?

Answer 29

IL-17 (Th17 cells) - neutrophil recruitment
IFN-gamma (Th1 cells) - macrophage recruitment
TNF-alpha, chemokines (lots of cells) - leukocyte recruitment

Question 30

What is rheumatoid arthritis?

Answer 30

An inflammatory disease involving joints of the extremities, characterized by inflammation of the synovium
Mediated by CD4+ Th1 and Th17 cells in the joint
Pathogenesis not fully understood

Question 31

What is multiple sclerosis? What are the symptoms?

Answer 31

An autoimmune disease of the CNS which involves CD4+ Th1 and Th17 cells that react against self myelin antigens
This results in CNS inflammation and activation of macrophages
This causes destruction of the myelin sheath, abnormal nerve conduction, and neurologic deficits
Symptoms - weakness, paralysis, and ocular problems

Question 32

What HLA allele is strongly associated with MS?

Answer 32

HLA-DR2

Question 33

What is epitope spreading? How is it relevant to the pathogenesis of MS?

Answer 33

Destruction of tissue and inflammation leads to the release of new, previously sequestered protein antigens
These activate more autoreactive T cells
This is why MS can persist in genetically susceptible hosts, and is difficult to treat

Question 34

What is type 1 diabetes mellitus?

Answer 34

A deficiency of insulin resulting from immune-mediated destruction of insulin-producing beta cells in the pancreas
Early stage - CD4 and CD8 T cell infiltration and islet cellular necrosis
Advanced stages - multiple immune defects directed against islet cells

Question 35

What HLA allele is strongly associated with DM1?

Answer 35

HLA-DR3 and/or HLA-DR4

Question 36

What is a granuloma?

Answer 36

A chronic delayed-type hypersensitivity reaction with fibrosis
Develops if a Th1 response activates macrophage, but fails to eliminate the threat
Body attempts to contain pathogens that cannot be eliminated
Can cause significant tissue injury and functional impairment

Question 37

What types of cells are a hallmark of granulomas?

Answer 37

Epithelioid cells - activated, hypertrophied macrophages that resemble skin epithelial cells
Multinucleated giant cells - fused macrophages

Question 38

What type of necrosis is a hallmark of a granuloma?

Answer 38

Caseating necrosis

Question 39

What is sarcoidosis?

Answer 39

Disease characterized by non-necrotizing granulomas that can form in almost any organ, especially the lungs and lymph nodes
Often resolve spontaneously
10% of patients develop serious disability - lung scarring, respiratory failure