Path Book: Chapter 4 Diseases of the Immune System

Question 1

What are Type I hypersensitivity reactions?

Answer 1

A tissue reaction that occurs rapidly (typically within minutes) after the interaction of antigen with IgE antibody that is bound to the surface of mast cells in a sensitized host.

Question 2

What is the first thing that happens in most Type I reactions?

Answer 2

Activation of TH2 cells and production of IgE antibody

Question 3

Why do some allergens promote hypersensitivity and others don’t?

Answer 3

Variables that probably contribute to the strong TH2 responses to allergens include the route of entry, dose, and chronicity of antigen exposure, and the genetic makeup of the host.

It is not clear if allergenic substances also have unique structural properties that endow them with the ability to elicit TH2 responses.

Question 4

T or F. Immediate hypersensitivity is the prototypical TH2-mediated reaction.

Answer 4

T.

Question 5

How do IgE bind to mast cells following an initial exposure to an allergen?

Answer 5

Mast cells express a high-affinity receptor for the Fc portion of the ε heavy chain of IgE, called FcεRI.

Question 6

What is the main mediator of Type I reactions?

Answer 6

The granules of mast cells contain histamine, which is released within seconds or minutes of activation.

Question 7

What does release of histamine cause?

Answer 7

Histamine causes vasodilation, increased vascular permeability, smooth muscle contraction, and increased secretion of mucus.

Question 8

What are the phases of Type I reactions?

Answer 8

(1) the immediate response, characterized by vasodilation, vascular leakage, and smooth muscle spasm, usually evident within 5 to 30 minutes after expo- sure to an allergen and subsiding by 60 minutes; and
(2) a second, late-phase reaction that usually sets in 2 to 8 hours later and may last for several days and is characterized by inflammation as well as tissue destruction, such as mucosal epithelial cell damage.

Question 9

T or F. An immediate hypersensitivity reaction may occur as a systemic disorder or as a local reaction.

Answer 9

T. The nature of the reaction is often determined by the route of antigen exposure. E.g. systemic exposure to venom or drugs will lead to systemic symptoms

Local reactions generally occur when the antigen is con- fined to a particular site, such as skin (contact, causing urticaria), gastrointestinal tract (ingestion, causing diar- rhea), or lung (inhalation, causing bronchoconstriction)

Question 10

What are some common symptoms of Type I reactions?

Answer 10

Within minutes of the exposure in a sensitized host, itching, urticaria (hives), and skin erythema appear, followed in short order by profound respiratory difficulty caused by pulmonary bronchoconstriction and accentuated by hypersecretion of mucus.

In addition, the musculature of the entire Gl tract may be affected, with resultant vomiting, abdominal cramps, and diarrhea. Without immediate intervention, there may be systemic vasodilation with a fall in blood pressure (anaphylactic shock), and the patient may progress to circulatory collapse and death within minutes.

Question 11

What is the basis of Type III hypersensitivities?

Answer 11

Antigen–antibody (immune) complexes that are formed in the circulation may deposit in blood vessels, leading to complement activation and acute inflammation.

The mere formation of immune complexes does not equate with hypersensitivity disease; small amounts of antigen– antibody complexes may be produced during normal immune responses and are usually phagocytosed and destroyed. It is only when these complexes are produced in large amounts, persist, and are deposited in tissues that they are pathogenic

Question 12

What are the main organs affected by SLE?

Answer 12

clinically variable; can affect any organ but skin, kidneys, joints, and heart are most common

Question 13

Is SLE more common in men or women?

Answer 13

9:1 women

Question 14

When is SLE particularly common in women?

Answer 14

during childbearing years. SLE is 10 times more common in women during reproductive years than in men of similar ages but only 2 to 3 times more common in women during childhood or after the age of 65.

Question 15

Is it sex hormones that increases the risk of SLE flare in childbearing aged women?

Answer 15

No, that was the thought but treatment of women with oral contraceptives containing high doses of estrogen and progesterone did not influence the frequency or severity of disease flares, suggesting that factors other than hormones may account for the increased risk of this disease in women.

Question 16

What drugs can cause SLE flare-ups?

Answer 16

procainamide and hydralazine can induce an SLE-like disease, although typically glomerulonephritis does not develop. These drugs cause demethylation of DNA, which could influence the expression of a variety of genes involved in the development of autoimmunity, or the ability of DNA to activate host cells.

Question 17

Most organ damage in SLE is caused by what?

Answer 17

Most organ damage in SLE is caused by immune complex deposition. Skin and kidney biopsies from patients with SLE typically demonstrate diffuse and heavy granular deposits of complement and immunoglobulin. These deposits of immune complexes had been thought to cause tissue damage by activating the classical com- plement pathway (type III hypersensitivity)

Question 18

Since SLE can be an immune complex disease, what blood factors should be reduced during flareups?

Answer 18

75% of patients will have reduced serum levels of C3 and C4 at the time of SLE flares, presumably because complement is being activated and consumed faster than it can be produced.

Question 19

What are the main symptoms associated with SLE?

Answer 19

Typically, the patient is a young woman with some, but rarely all, of the following features: a butterfly rash over the face, fever, pain and swelling in one or more peripheral joints (hands and wrists, knees, feet, ankles, elbows, shoulders), pleuritic chest pain, and photo- sensitivity.

Question 20

Rejection of allografts is a response mainly to ______.

Answer 20

MHC molecules, which are so polymorphic that most individuals in an outbred population differ in at least some of the MHC molecules they express (except, of course, for identical twins).

Question 21

Why do foreign MHC molecules result in rejection?

Answer 21

Direct recognition. Host T cells directly recognize the allo- geneic (foreign) MHC molecules that are expressed on graft cells. Direct recognition of foreign MHC seems to violate the rule of MHC restriction, which states that in every individual, all of the T cells are educated to recognize foreign antigens displayed by only that individual’s MHC molecules. It is postulated that allogeneic MHC molecules (with any bound peptides) structurally mimic self MHC and foreign peptide, and so direct recognition of the allogeneic MHC is essentially an immunologic cross-reaction.

Question 22

What are major cells responsible for direct recognition?

Answer 22

Because DCs in the graft express high levels of MHC as well as costimulatory molecules, they are believed to be the major culprits contributing to direct recognition.

Question 23

T or F. Both T cells and antibodies reactive with the graft are involved in the rejection of most solid-organ allografts

Answer 23

T.

Question 24

How do T cells mediate solid-organ great rejection?

Answer 24

CTLs kill cells in the grafted tissue, causing parenchymal and endothelial cell death. Cytokine-secreting CD4+ T cells trigger inflammatory reactions resembling DTH in the tissues and blood vessels, with local accumulation of mononuclear cells (lymphocytes and macrophages). Activated microphages can injure graft cells and vasculature. The microvascular injury also results in tissue ischemia, which contributes to graft destruction.

Question 25

What is Hyperacute rejection?

Answer 25

a special form of rejection occurring if pre-formed anti-donor antibodies are present in the circulation of the host before transplantation. This may happen in multiparous women who have anti-HLA anti- bodies against paternal antigens encountered during pregnancy, or in individuals exposed to foreign HLA (on platelets or leukocytes) from previous blood transfusions.

Obviously, such antibodies also may be present in a patient who has previously rejected an organ transplant. Subse- quent transplantation in such patients will result in imme- diate rejection (within minutes to hours) because thecirculating antibodies rapidly bind to the endothelium of the grafted organ, with resultant complement activation and vascular thrombosis.

Question 26

Because HLA molecules are the major targets in transplant rejection, better matching of the donor and the recipient improves graft survival.

Answer 26

The benefits of HLA matching are most dramatic for living related donor kidney transplants, and survival improves with increasing number of loci matched.

Question 27

What is Graft-Versus-Host Disease (GVHD)?

Answer 27

This occurs when immunologically competent T cells (or their precursors) are transplanted into recipients who are immunologically compromised. Although GVHD happens most commonly in the setting of allogeneic HSC transplantation (usually involving minor histocompatibility mismatches between donor and recipient), it also may occur after transplanta- tion of solid organs rich in lymphoid cells (e.g., the liver) or after transfusion of nonirradiated blood.

Question 28

Are R5 or X4 strains of HIV more common?

Answer 28

Of interest, approximately 90% of HIV infections initially are transmitted by R5 strains. Over the course of infection, however, X4 viruses gradually accumulate; these are espe- cially virulent and are responsible for T cell depletion in the final, rapid phase of disease progression. It is thought that during the course of HIV infection, R5 strains evolve into X4 strains, as a result of mutations in genes that encode gp120.