PATHOLOGICAL FINDINGS IN HUMAN AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME

The defects in lymphocyte apoptosis that underlie the autoimmune lymph oproliferative syndrome (ALPS) are usually attributable to inherited m utations of the CD95 (Fas) gene. In this report, we present the histop athological and immunophenotypic features seen hi 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 marke d paracortical hyperplasia. Interfollicular areas were expanded and po pulated by T cell receptor-alpha beta CD3(+) CD4(-)CD8(-) (double-nega tive, DN) T cells that were negative for CD45RO. CD45RA(+) T cells wer e increased in all cases studied. The paracortical infiltrate was a re sult of both reduced apoptosis and increased proliferation, as measure d by in situ detection of DNA fragmentation and staining with MIB-1, r espectively. The paracortical proliferation may be extensive enough to suggest a diagnosis of malignant lymphoma. Many of the paracortical l ymphocytes expressed markers associated with cytotoxicity, such as per forin, TIA-1, and CD57, CD25 was negative. in addition, most lymph nod es exhibited florid follicular hyperplasia, often with focal progressi ve transformation of germinal centers; in some cases, follicular invol ution was seen. A polyclonal plasmacytosis also was present, The splee ns were markedly enlarged, more than 10 times normal size. There was e xpansion of both white pulp and red pulp, with increased DN T cells. D N T cells also were observed in Liver biopsies exhibiting portal triad itis, 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 h istopathological 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 lymphocyt e predominance Hodgkin's disease, respectively).