Immunopathology of the X-linked lymphoproliferative syndrome

The immunopathogenesis of 25 kindreds affecting 100 males with the X-linked lymphoproliferative syndrome (XLP) is being studied comprehensively by our registry and laboratory group. XLP is a combined variable immune deficiency with Epstein-Barr virus (EBV) induced phenotypes of: (1) fatal infectious mononucleosis (IM), (2) chronic IM progressive to malignant lymphoma, (3) acute IM progressive to acquired agammaglobulinemia or (4) malignant lymphoma. Cytogenetic studies of peripheral blood lymphocytes from 15 surviving males and 21 carrier females reveal random karyotype errors in several kindreds. Often polyclonal Ig or selective IgM increases and lymphocytosis with plasmacytoid forms typifies the IM phenotypes. Weakly reactive EBV-specific antibodies are found and anti-EB nuclear antigen is lacking. Antibodies to EBV are paradoxically elevated in female carriers. Initially all lymphoid tissues show immunoblastic proliferation with plasma cell differentiation and focal to extensive necrosis. Thymus gland and other lymphoid organs become depleted in T cell regions and Hassall's corpuscles may become destroyed. Multinucleated giant cells may be seen destroying the corpuscles or calcified corpuscles are found. The lymphoid infiltrates and lesions resemble graft-versus-host response in the fatal IM phenotype. Extensive necrosis in lymph nodes and deficient Ig secretion of B-cells characterize acquired agammaglobulinemia phenotypes. The malignant lymphomas span the spectrum of B cell differentiation with most being immunoblastic sarcomas. One case probably was monoclonal thus far, others are being studied. EBV DNA hybridization of tissues from 7 patients with fatal IM revealed 1 to 20 EBV genome equivalents per cell. The patients lacked appropriate EBV antibody responses. Our studies of XLP support the hypothesis that immune deficiency the EBV permits chronic and fatal lymphoproliferative diseases in XLP following EBV infections. Owing to this knowledge, rational bases for prevention by genetic counseling and by providing high titer gammaglobulin and antiviral therapy is being attempted.