Pathological Findings in Human Autoimmune Lymphoproliferative Syndrome

M Lim

S Straus

J Dale

T Fleisher

M Lenardo+4 authors

From the Laboratory of Pathology* and the Genetic Epidemiology Branch** of the National Cancer Institute, the Laboratories of Clinical Investigation,† Immunoregulation,§ and Immunology^{of the National Institute of Allergy and Infectious Diseases, the Warren Grant Magnuson Clinical Center,‡ and the Genetics and Molecular Biology Branch}¶ of the National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland

Accepted 1998 Jul 24.

Abstract

The defects in lymphocyte apoptosis that underlie the autoimmune lymphoproliferative syndrome (ALPS) are usually attributable to inherited mutations of the CD95 (Fas) gene. In this report, we present the histopathological and immunophenotypic features seen in the lymph nodes (n = 16), peripheral blood (n = 10), bone marrow (n = 2), spleen (n = 3), and liver (n = 2) from 10 patients with ALPS. Lymph nodes showed marked paracortical hyperplasia. Interfollicular areas were expanded and populated by T cell receptor-αβ CD3^CD4^CD8^{(double-negative, DN) T cells that were negative for CD45RO. CD45RA}^{T cells were increased in all cases studied. The paracortical infiltrate was a result of both reduced apoptosis and increased proliferation, as measured by}in situ detection of DNA fragmentation and staining with MIB-1, respectively. The paracortical proliferation may be extensive enough to suggest a diagnosis of malignant lymphoma. Many of the paracortical lymphocytes expressed markers associated with cytotoxicity, such as perforin, TIA-1, and CD57. CD25 was negative. In addition, most lymph nodes exhibited florid follicular hyperplasia, often with focal progressive transformation of germinal centers; in some cases, follicular involution was seen. A polyclonal plasmacytosis also was present. The spleens were markedly enlarged, more than 10 times normal size. There was expansion of both white pulp and red pulp, with increased DN T cells. DN T cells also were observed in liver biopsies exhibiting portal triaditis. In the peripheral blood, the T cells showed increased expression of HLA-DR and CD57 but not CD25. CD45RA^{T cells were increased in the four cases studied. Polyclonal B cell lymphocytosis with expansion of CD5}^{B cells was a characteristic finding. Taken together, the histopathological and immunophenotypic findings, particularly in lymph nodes and peripheral blood, are sufficiently distinctive to suggest a diagnosis of ALPS. Of note, two affected family members of one proband developed lymphoma (T-cell-rich B-cell lymphoma and nodular lymphocyte predominance Hodgkin’s disease, respectively).}

Abstract

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder characterized by generalized, nonmalignant lymphadenopathy, hypergammaglobulinemia, lymphocytosis, splenomegaly, and autoimmune phenomena. A distinct feature of ALPS, and an early clue to its nature, is the occurrence of markedly increased numbers and percentage of T cell receptor (TCR)-αβ CD4^CD8^{, double-negative (DN) T cells in the circulation and lymphoid tissues. Sneller et al}¹ first reported a detailed clinical and immunological study of two patients, recognizing similarities to the MRL and C3H/Hej strains of mice possessing the lpr and gld mutations, respectively. Genetic elucidation of the lpr and gld loci as representing recessive mutations in the genes encoding CD95 (Fas/Apo-1) and CD95L (FasL), respectively,^2-4 led to the discovery of functional CD95 mutations in ALPS patients.^5-8 With the ability to diagnose specific CD95 mutations in ALPS cases, it was appreciated that patients affected with this disorder had been included in published series by a number of investigators of undefined chronic lymphoproliferation or splenomegaly with associated autoimmune phenomena.^9,10

CD95 is a 48-kd type I transmembrane protein belonging to the tumor necrosis factor receptor family. Interaction of CD95 and its ligand plays a critical role in controlling the homeostasis of peripheral lymphocytes by inducing signals leading to cellular apoptosis; thus, aberrations in this interaction would be expected to impair the apoptosis of normal and autoreactive lymphocytes. Indeed, mice bearing the lpr or gld mutations, who thus have defective expression of CD95 or its ligand, respectively, develop massive lymphoid hyperplasia and autoimmunity.^11-13

In vitro studies of B and T cells from ALPS patients and their family members verify that in humans, as well as in mice, CD95 mutations lead to defective lymphocyte apoptosis. The precise role of CD95 in lymphocyte homeostasis in these individuals is not completely understood. This fact is illustrated by the wide spectrum of clinical and immunological findings in ALPS patients and the occurrence of family members who possess identical mutations and defective in vitro apoptosis but few or no clinical signs of ALPS.¹⁴

In this study, we report the spectrum of histological and immunophenotypic features of 10 patients with ALPS. The potential functional properties of expanded DN T cells characteristic of this syndrome are also discussed.

CGP, cytotoxic granule-associated protein.

*Used in paraffin sections only.

^{Used in flow cytometry only.}

M, male; F, female.

ND: Not determined; NA, not available.

*Percentage of DN T cells that also express CD45RA.

^{Percentage of CD20 cells that also express CD5.}

Acknowledgments

We gratefully acknowledge the assistance of Drs. Laszlo Krenacs and Douglas W. Kingma, Laboratory of Pathology, NCI, for assistance with immunohistochemical and in situ hybridization studies, respectively.

Acknowledgments

Footnotes

Address reprint requests to Dr. Elaine S. Jaffe, Hematopathology Section, Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Building 10, Room 2N 202, 10 Center Drive MSC-1500, Bethesda, MD 20892. E-mail: .vog.hin@effaj.eniale

M.S. Lim is a recipient of a clinical fellowship from the Medical Research Council of Canada, Alberta Heritage Foundation for Medical Research, and the Fogarty Visiting Fellowship from the National Institutes of Health.

Footnotes

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