Disease Antigen Involved Clinicopathologic Manifestations

Systemic lupus erythematosus DNA, nucleoproteins, others Nephritis, arthritis, vasculitis

Polyarteritis nodosa Hepatitis B virus surface antigen (in some cases) Vasculitis

Poststreptococcal glomerulonephritis Streptococcal cell wall antigen(s); may be "planted" in glomerular basement

membrane

Nephritis

Acute glomerulonephritis Bacterial antigens (Treponema); parasite antigens (malaria, schistosomes); tumor

antigens

Nephritis

Reactive arthritis Bacterial antigens (Yersinia) Acute arthritis

Arthus reaction Various foreign proteins Cutaneous vasculitis

Serum sickness Various proteins, e.g., foreign serum (anti-thymocyte globulin) Arthritis, vasculitis, nephritis

occurrence of diseases caused by immune complexes was suspected in the early 1900s by a physician named Clemens von Pirquet. Patients with diphtheria infection were being treated

with serum from horses immunized with the diphtheria toxin. Von Pirquet noted that some of these patients developed arthritis, skin rash, and fever, and the symptoms appeared more

rapidly with repeated injection of the serum. Von Pirquet concluded that the treated patients made antibodies to horse serum proteins, these antibodies formed complexes with the injected

proteins, and the disease was due to the antibodies or immune complexes. He called this disease "serum disease"; it is now known as serum sickness. In modern times the disease is

infrequent, but it is an informative model that has taught us a great deal about systemic immune complex disorders.

For the sake of discussion, the pathogenesis of systemic immune complex disease can be divided into three phases: (1) formation of antigen-antibody complexes in the circulation; (2)

deposition of the immune complexes in various tissues, thus initiating; and (3) an inflammatory reaction at the sites of immune complex deposition ( Fig. 6-15 ). The first phase is initiated

by the introduction of antigen, usually a protein, and its interaction with immunocompetent cells, resulting in the formation of antibodies approximately a week after the injection of the

protein. These antibodies are secreted into the blood, where they react with the antigen still present in the circulation to form antigen-antibody complexes. In the second phase, the

circulating antigen-antibody complexes are deposited in various tissues.

The factors that determine whether immune complex formation will lead to tissue deposition and disease are not fully understood, but two possible influences are the size of the immune

complexes and the functional status of the mononuclear phagocyte system:

• Large complexes formed in great antibody excess are rapidly removed from the circulation by the mononuclear phagocyte system and are therefore relatively harmless. The most

pathogenic complexes are of small or intermediate size (formed in slight antigen excess), which bind less avidly to phagocytic cells and therefore circulate longer.

• Because the mononuclear phagocyte system normally filters out the circulating immune complexes, its overload or intrinsic dysfunction increases the probability of persistence of

immune complexes in circulation and tissue deposition.

In addition, several other factors, such as charge of the immune complexes (anionic versus cationic), valency of the antigen, avidity of the antibody, affinity of the antigen to various tissue

components, three-dimensional (lattice) structure of the complexes, and hemodynamic factors, influence the tissue deposition of complexes. Because most of these influences have been

investigated with reference to deposition of immune complexes in the glomeruli, they are discussed further in Chapter 20 . In addition to the renal glomeruli, the favored sites of immune

complex deposition are joints, skin, heart, serosal surfaces, and small blood vessels. For complexes to leave the microcirculation and deposit in the vessel wall, an increase in vascular

permeability must occur. This is believed to occur when immune complexes bind to inflammatory cells through their Fc or C3b receptors and trigger release of vasoactive mediators as well

as permeability-enhancing cytokines. Mast cells may also be involved in this phase of the reaction.

Once complexes are deposited in the tissues, they initiate an acute inflammatory reaction (third phase). During this phase (approximately 10 days after antigen administration), clinical

features such as fever, urticaria, arthralgias, lymph node enlargement, and proteinuria appear.

Wherever complexes deposit, the tissue damage is similar. Two mechanisms are believed to cause inflammation at the sites of deposition ( Fig. 6-16 ): (1) activation of the complement

cascade, and (2) activation of neutrophils and macrophages through their Fc receptors. As discussed in Chapter 2 , complement activation promotes inflammation mainly by production of

chemotactic factors, which direct the migration of polymorphonuclear leukocytes and monocytes

Figure 6-15Schematic illustration of the three sequential phases in the induction of systemic immune complex-mediated disease (type III hypersensitivity).

Figure 6-16Pathogenesis of immune complex-mediated tissue injury. The morphologic consequences are depicted as boxed areas.

Figure 6-17Immune complex vasculitis. The necrotic vessel wall is replaced by smudgy, pink "fibrinoid" material. (Courtesy of Dr. Trace Worrell, Department of Pathology, University of

Texas Southwestern Medical School, Dallas, TX.)

Figure 6-18Mechanisms of T cell-mediated (type IV) hypersensitivity reactions. A, In delayed type hypersensitivity reactions, CD4+ T cells (and sometimes CD8+ cells) respond to tissue

antigens by secreting cytokines that stimulate inflammation and activate phagocytes, leading to tissue injury. B, In some diseases, CD8+ cytolytic T lymphocytes (CTLs) directly kill tissue

cells. APC, antigenpresenting cell.

TABLE 6-6-- Examples of T Cell-Mediated (Type IV) Hypersensitivity

Date: 2016-04-22; view: 831