Immunologic Factors.

With all the immunologic findings in SLE patients, there can be little doubt that some fundamental derangement of the immune system is involved in the pathogenesis of SLE. Although a

variety of immunologic abnormalities affecting both T cells and B cells have been detected in patients with SLE, it has been difficult to relate any one of them to the causation of this

disease. For years, it had been thought that an intrinsic B-cell hyperactivity is fundamental to the pathogenesis of SLE. Polyclonal B-cell activation can be readily demonstrated in patients

with SLE and in murine models of this disease. Molecular analyses of anti-double-stranded DNA antibodies, however, strongly suggest that pathogenic autoantibodies are not derived from

polyclonally activated B cells. Instead, it appears that the production of tissue-damaging antibodies is driven by self-antigens and results from an antigen-specific helper T cell-dependent Bcell

response with many characteristics of responses to foreign antigens.[66] These observations have shifted the onus of driving the autoimmune response squarely on helper T cells.[66A]

Based on these findings, a model for the pathogenesis of SLE has been proposed ( Fig. 6-30 ). Other contributing factors include defective clearance of apoptotic cells, mentioned above,

and dysregulation of cytokines, notably interferons.[61] SLE is a heterogeneous disease, however, and as mentioned earlier, the production of different autoantibodies is regulated by

distinct genetic factors. Hence, there may well be distinct immunoregulatory disturbances in patients with different genetic backgrounds and autoantibody profiles.[67]

Regardless of the exact sequence by which autoantibodies are formed, they are clearly the mediators of tissue injury. Most of the visceral lesions are mediated by immune complexes (type

III hypersensitivity). DNA-anti-DNA complexes can be detected in the glomeruli and small blood vessels. Low levels of serum complement and granular deposits of complement

Figure 6-30Model for the pathogenesis of systemic lupus erythematosus. (Modified from Kotzin BL: Systemic lupus erythematosus. Cell 65:303, 1996. Copyright 1996, Cell Press.)

TABLE 6-10-- Clinical and Pathologic Manifestations of Systemic Lupus Erythematosus

Clinical Manifestation Prevalence in Patients, %

Hematologic 100

Arthritis •90

Skin •85

Fever •83

Fatigue •81

Weight loss •63

Renal •50

Central nervous system •50

Pleuritis •46

Myalgia •33

Pericarditis •25

Gastrointestinal •21

Paynaud phenomenon •20

Ocular •15

Peripheral neuropathy •14

lesions result from the deposition of immune complexes and are found in the blood vessels, kidneys, connective tissue, and skin.

An acute necrotizing vasculitis involving small arteries and arterioles may be present in any tissue.[68] The arteritis is characterized by fibrinoid deposits in the vessel walls. In chronic

stages, vessels undergo fibrous thickening with luminal narrowing.

Kidney.

The kidney is a frequent target of injury in SLE. The principal mechanism of injury is immune complex deposition in renal structures, including glomeruli, tubular and peritubular capillary

basement membranes, and larger blood vessels. Other forms of injury may include a thrombotic process involving the glomerular capillaries and extraglomerular vasculature, thought to be

caused by antiphospholipid antibodies.

A morphologic classification of the patterns of immune complex-mediated glomerular injury in SLE has proven to be clinically useful.[69] There are several versions of the World Health

Organization (WHO) classification of lupus nephritis, but in all, five patterns are recognized: (1) minimal or no detectable abnormalities (class I), which is rare, seen in renal biopsies from

less than 5% of SLE patients; (2) mesangial lupus glomerulonephritis (class II); (3) focal proliferative glomerulonephritis (class III); (4) diffuse proliferative glomerulonephritis (class IV);

and (5) membranous glomerulonephritis (class V). None of these patterns is specific for lupus.

Mesangial lupus glomerulonephritisis characterized by mesangial cell proliferation and lack of involvement of glomerular capillary walls. It is seen in 10% to 25% of patients, most of

whom have minimal clinical manifestations, such as mild hematuria or transient proteinuria. There is a slight to moderate increase in the intercapillary mesangial matrix as well as in the

number of mesangial cells. Despite the mild histologic changes, granular mesangial deposits of immunoglobulin and complement are always present. Such deposits presumably

reflect the earliest change because filtered immune complexes accumulate primarily in the mesangium. The other changes to be described are usually superimposed on the mesangial

changes.

Focal proliferative glomerulonephritisis seen in 20% to 35% of patients. It is a focal lesion, affecting fewer than 50% of the glomeruli and generally only portions of each glomerulus.

Typically, one or two tufts in an otherwise normal glomerulus exhibit swelling and proliferation of endothelial and mesangial cells, infiltration with neutrophils, and sometimes fibrinoid

deposits and intracapillary thrombi ( Fig. 6-31 ). Occasionally, affected glomeruli exhibit global injury. Focal lesions are associated with hematuria and proteinuria. In some patients, the

nephritis progresses to diffuse proliferative disease.

Diffuse proliferative glomerulonephritisis the most serious of the renal lesions in SLE, occurring in 35% to 60% of patients who undergo biopsy. Anatomic changes are dominated by

proliferation of endothelial, mesangial and, sometimes, epithelial cells ( Fig. 6-32 ), producing in some cases epithelial crescents that fill the Bowman space ( Chapter 20 ). The presence of

fibrinoid necrosis, crescents, prominent infiltration by leukocytes, cell death as indicated by apoptotic bodies, and hyaline thrombi indicates active disease. Most or all glomeruli are

involved in both kidneys, and the entire glomerulus is frequently affected. Patients with diffuse lesions are usually overtly symptomatic, showing microscopic or gross hematuria as well as

proteinuria that is severe enough to cause the nephrotic syndrome in more than 50% of patients. Hypertension and mild to severe renal insufficiency are also common.

Membranous glomerulonephritisis a designation given to glomerular disease in which the principal histologic change consists of widespread thickening of the capillary walls. The

lesions are similar to those encountered in idiopathic membranous glomerulonephritis, described more fully in Chapter 20 . This type of lesion is seen in 10% to 15% of patients with

Figure 6-31Lupus nephritis. There are two focal necrotizing lesions in the glomerulus (arrowheads). (Courtesy of Dr. Helmut Rennke, Department of Pathology, Brigham and Women's

Hospital, Boston, MA.)

Figure 6-32Lupus nephritis, diffuse proliferative type. Note the marked increase in cellularity throughout the glomerulus. (Courtesy of Dr. Helmut Rennke, Department of Pathology,

Brigham and Women's Hospital, Boston, MA.)

Figure 6-33Immunofluorescence micrograph stained with fluorescent anti-IgG from a patient with diffuse proliferative lupus nephritis. One complete glomerulus and part of another one

are seen. Note the mesangial and capillary wall deposits of IgG. (Courtesy of Dr. Helmut Rennke, Department of Pathology, Brigham and Women's Hospital, Boston, MA.)

Figure 6-34Electron micrograph of a renal glomerular capillary loop from a patient with systemic lupus erythematosus nephritis. Subendothelial dense deposits correspond to "wire loops"

seen by light microscopy. Deposits are also present in the mesangium. (Courtesy of Dr. Jean Olson, Department of Pathology, University of California San Francisco, San Francisco, CA.)

Figure 6-35Lupus nephritis showing a glomerulus with several "wire loop" lesions representing extensive subendothelial deposits of immune complexes. (Periodic acid-Schiff [PAS]

stain.) (Courtesy of Dr. Helmut Rennke, Department of Pathology, Brigham and Women's Hospital, Boston, MA.)

Figure 6-36Systemic lupus erythematosus involving the skin. A, An H&E-stained section shows liquefactive degeneration of the basal layer of the epidermis and edema at the

dermoepidermal junction. (Courtesy of Dr. Jag Bhawan, Boston University School of Medicine, Boston, MA.) B, An immunofluorescence micrograph stained for IgG reveals deposits of

immunoglobulin along the dermal-epidermal junction. (Courtesy of Dr. Richard Sontheimer, Department of Dermatology, University of Texas Southwestern Medical School, Dallas, TX.)

Figure 6-37Libman-Sacks endocarditis of the mitral valve in lupus erythematosus. The vegetations attached to the margin of the thickened valve leaflet are indicated by arrows. (Courtesy

of Dr. Fred Schoen, Department of Pathology, Brigham and Women's Hospital, Boston, MA.)

Figure 6-38Sjögren syndrome. A, Enlargement of the salivary gland. (Courtesy of Dr. Richard Sontheimer, Department of Dermatology, University of Texas Southwestern Medical

School, Dallas, TX.) B, Intense lymphocytic and plasma cell infiltration with ductal epithelial hyperplasia in a salivary gland. (Courtesy of Dr. Dennis Burns, Department of Pathology,

University of Texas Southwestern Medical School, Dallas, TX.)

Figure 6-39Schematic illustration of the possible mechanisms leading to systemic sclerosis.

Figure 6-40Systemic sclerosis. A, Normal skin. B, Skin biopsy from a patient with systemic sclerosis. Note the extensive deposition of dense collagen in the dermis with virtual absence of

appendages (e.g. hair follicles) and foci of inflammation (arrow).

Figure 6-41Advanced systemic sclerosis. The extensive subcutaneous fibrosis has virtually immobilized the fingers, creating a clawlike flexion deformity. Loss of blood supply has led to

cutaneous ulcerations. (Courtesy of Dr. Richard Sontheimer, Department of Dermatology, University of Texas Southwestern Medical School, Dallas, TX.)

TABLE 6-11-- Examples of Infections in Immunodeficiencies

Date: 2016-04-22; view: 906