Howard R. Smith

Bullous eruption of systemic lupus erythematosus. Dramatic response to dapsone therapy.

Four patients with systemic lupus erythematosus developed a nonpruritic vesiculobullous eruption that was unresponsive to high-dose systemic corticosteroid therapy. In three patients the eruption was not associated with a flare of systemic disease. Biopsy results showed neutrophilic microabscesses at the dermal papillary tips and perivascular lymphohistiocytic infiltrates. Direct immunofluorescence of normal appearing skin not exposed to the sun was positive in all four patients. Due to the unresponsiveness to corticosteroid therapy and the striking histologic resemblance to dermatitis herpetiformis, each of the patients was treated with dapsone. Within 24 hours each patient had prompt cessation of the appearance of new lesions. Improvement of the eruption did not correlate with improvement of the systemic manifestations of their lupus erythematosus. The rapid response to dapsone therapy suggests that dapsone is useful in treating bullous lesions of systemic lupus erythematosus.

Clonality of angioimmunoblastic lymphadenopathy and implications for its evolution to malignant lymphoma.

To investigate the relationship of the lymphoid hyperplasia of angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) to supervening malignant lymphoma, we subjected DNA from lymph nodes and peripheral blood mononuclear cells from five AILD patients to Southern blot analysis to detect clonal rearrangements of immunoglobulin and T-cell receptor genes. Lymph nodes and peripheral blood from AILD patients were found to contain clones of lymphoid cells harboring either immunoglobulin or T-cell receptor gene rearrangements that, in some instances, regressed during the course of disease. A lymph node from one patient was involved by immunoblastic lymphoma and manifested an additional gene rearrangement pattern not seen in premalignant specimens from that patient. In contrast, DNA obtained from normal peripheral blood mononuclear cells and 11 examples of other forms of lymphoid hyperplasia showed no gene rearrangements. As a disorder of cellular immunoregulation in which lymphoid cells may escape normal growth controls, AILD provides a natural model to dissect stages of lymphomagenesis in man.

Systemic lupus erythematosus: insights from animal models

Abstract Systemic lupus erythematosus is a multisystem, antibody-mediated, autoimmune disorder that occurs spontaneously in humans and mice. Genetic factors appear to play an important predisposing...

Cyclophosphamide-induced changes in the mrl-lpr/lpr mouse: effects upon cellular composition, immune function, and disease.

MRL-lpr/lpr mice develop massive lymphadenopathy with excessive proliferation of T cells and associated immune abnormalities. To examine whether to not the disease process is intrinsic and irreversible, an immunomodulatory drug, cyclophosphamide, was administered to 16-week-old, sick MRL-lpr/lpr mice. Analysis of lymph node cells by flow cytometry from injected and control MRL-lpr/lpr mice indicated that cyclophosphamide had a marked effect upon the lymphoid cellular composition. Whereas control lymph nodes had a very large number of abnormal dull Ly 1+ T cells and very few other cells, the cyclophosphamide-injected mice had normal T and B cells. The immune responses to a T-cell-dependent antigen, sheep red blood cells, and a T-cell mitogen, concanavalin A, were normalized in cyclophosphamide-injected mice as compared to controls. In addition, injected mice had prolonged survival, decreased arthritis, markedly reduced adenopathy and splenomegaly, improved renal histology, and significantly diminished autoantibody levels. This study suggests that the disease and associated immune abnormalities of MRL-lpr/lpr mice are reversible by selective elimination of the abnormal dull Ly 1+ T cells.

NIH conference. Angioimmunoblastic lymphadenopathy with dysproteinemia.

Angioimmunoblastic lymphadenopathy with dysproteinemia is a disorder characterized by a sudden onset of constitutional symptoms and lymphadenopathy. Patients often have hypergammaglobulinemia, autoantibodies, rashes, thrombocytopenia, or hemolytic anemia. Diagnosis requires a lymph node biopsy that shows architectural effacement, absence of germinal centers, arborization of postcapillary venules, and a polymorphous infiltrate that includes immunoblasts. Early in the disease, activated T cells in blood and lymph nodes stimulate B cells to proliferate and produce antibody. However, late in the disease, immune suppression may result from increased suppressor function. Clonal rearrangements, which are seen in all patients with regard to either the T-cell receptor beta-chain gene or immunoglobulin genes, have been followed by malignant transformation and frank lymphoma in some patients. Thus, this disorder stands partway between benign lymphoid proliferation and clonal lymphoid transformation. The prognosis of this disorder is poor; 75% of patients die within 2 years or develop a lymphoid malignancy. The rest usually go into a sustained remission. Current treatment with corticosteroid and immunosuppressive agents is unsatisfactory, especially because of late immunosuppression and predisposition to infections.

Analysis of B-cell subpopulations. I: Relationships among splenic xid, Ly 1+, and Lyb 5+ B cells

The phenotypic and functional relationships among the various B-cell subsets is of importance for better understanding studies of the immune system. In this report, the realm of B cells encompassed by Lyb 5, Ly 1, and xid has been examined through the use of the alloantiserum anti-Lyb 5, the unique functional properties of Ly 1+ B cells, and the spontaneous autoantibody producing congenic xid mice, NZB.xid. By functional and phenotypic analysis, we have shown that (i) Lyb 5- B cells and B cells of xid mice are largely, but not completely, overlapping; (ii) xid spleen cells contain a population which is Lyb 5+; (iii) Ly 1+ B cells fall largely in the Lyb 5+ compartment; and (iv) the autoantibody-producing Ly 1+ B cells are predominantly Lyb 5+.

Short communicationAnalysis of B-cell subpopulations: I. Relationships among Splenic xid, Ly 11+, and Lyb 5+ B cells

The phenotypic and functional relationships among the various B-cell subsets is of importance for better understanding studies of the immune system. In this report, the realm of B cells encompassed by Lyb 5, Ly 1, and xid has been examined through the use of the alloantiserum anti-Lyb 5, the unique functional properties of Ly 1+ B cells, and the spontaneous autoantibody producing congenic xid mice, NZB.xid. By functional and phenotypic analysis, we have shown that (i) Lyb 5- B cells and B cells of xid mice are largely, but not completely, overlapping; (ii) xid spleen cells contain a population which is Lyb 5+; (iii) Ly 1+ B cells fall largely in the Lyb 5+ compartment; and (iv) the autoantibody-producing Ly 1+ B cells are predominantly Lyb 5+.

Effects of induced anemia in normal and autoimmune mice

Normal and autoimmune mice were studied with regard to signals eliciting differentiation and division of bone marrow stem cells. The erythropoiesis induced by anemia following serial bleedings was analyzed in young autoimmune New Zealand Black (NZB) mice and non-autoimmune strains. No difference in the response to the stimulus created by anemia was noted between the strains. After serial bleedings as a stimulus to stem cell proliferation, a five-fold increase in numbers of proliferating spleen cells occurred in both NZB and DBA/2 strains; the increased proliferating spleen cells in both strains were non-lymphoid. The bled animals had decreased percentages of B cells. The production of autoantibodies was not significantly altered by the experimentally induced anemia. In contrast, anti-immunoglobulin activation of resting B cells was increased in response to anemia. Young mice which had experimentally induced anemia had several characteristics in common with old autoimmune NZB mice. Both old NZB mice and young anemic animals had splenomegaly, increased numbers of proliferating spleen cells, decrease in splenic Ly 5+ cells and an increase in splenic colony forming units (CFUs). The anemic normal strains of animals lacked other characteristics of old NZB mice such as hyperimmunoglobulinemia or autoantibody production or elevated CD5+B cell numbers. This work supports the concept that the increase in spleen cell number, proliferating spleen cells, CFUs and the increased percentages of non-Ly-5 cells (which include erythroid precursors) found in the spleens of old NZB mice may in part result from their autoimmune hemolytic anemia.

Splenic migration of xid and non-xid splenic B cells

The X-linked immune deficiency gene (xid) has been viewed as inducing either a deficiency in a B-cell subset or in B-cell maturation. The present experiments were performed in an attempt to better understand whether (a) xid B cells migrate differently from mature and immature non-xid B cells, and (b) whether the failure of mature B cells to be found in xid spleen, but not Peyers patches, is secondary to migratory differences, especially the possible inability of xid spleens to receive mature B cells. We employed the technique of internally fluorescein labeling donor cells and subsequent injection into recipients. Double labeling permitted analysis of B or T cells by two-color flow microfluorometry. Functional studies revealed that labeled cells appropriately responded to TI-1 and TI-2 antigens after migration. We found that (a) adult xid splenic B cells do not migrate to spleen as well as adult non-xid splenic B cells, (b) the migration of adult xid splenic B cells to spleen resembles that of neonatal (xid and non-xid) B cells, (c) equal masses of xid and non-xid spleens have an equal capacity to receive either xid or non-xid splenic B cells, and (d) the migration of xid and non-xid T cells is similar. These results suggest that xid B cells do not migrate normally, but that migratory differences cannot account for the failure of mature B cells to be found in xid spleens.

HLA Antigens in Angioimmunoblastic Lymphadenopathy

Excerpt To the editor: Angioimmunoblastic lymphadenopathy is a rare clinicopathologic entity that is characterized by lymphadenopathy, systemic autoimmune features, and a high potential for lymphoi...