Cd13-Specific Autoimmunity in Cytomegalovirus-Infected Immunocompromised Patients1

Abstract

Cytomegalovirus (CMV) infection has been suggested to be associated with various autoimmune manifestations, such as hemolytic anemia, granulocytopenia, and the formation of autoantibodies. Earlier we found that CMV is associated with a human protein, CD13 (aminopeptidase N), emanating from CMV-infected cells and serving an important function during CMV infection of susceptible cells. We hypothesized that CD13 might become immunogenic if presented to the immune system as a part of the CMV virion. The presence of CD13-specific antibodies was tested using a microcytotoxicity assay against CD13-positive human monocytes, or by flow cytometric assays against mouse cells transfected with human CD13; specificity was assessed by specific blocking with monoclonal antibodies. CD13 reactivity was also demonstrated in immunoprecipitation experiments. CD13-specific antibodies were identified in 15 of 33 bone marrow transplant patients, but exclusively in patients who had experienced either CMV disease (9/10) or CMV viremia (6/9), and appeared at the time of CMV detection. None of the remaining 14 patients without signs of CMV infection were positive for CD13 antibodies (P<0.0001). No antibody of this specificity was found in any of the control individuals (0/24), including patients with various autoimmune diseases, CMV-seropositive or -seronegative healthy individuals, and patients with acute EBV or HSV-1 infections. Thus, the CMV-associated autoantigen CD13 is immunogenic during CMV infection in bone marrow transplant patients. A specific response against autoantigens associated with infectious virus particles is suggested as a new and general mechanism to explain virus-induced autoimmune manifestations in man.

Response to steroids inde novoautoimmune hepatitis after liver transplantation

“…Bystander activation of macrophages and T lymphocytes, superantigen effects of bacterial products, and molecular mimicry processes are other factors that may occur during infection. 24,28,29 A distinctive feature of LTX is the need of immunosuppression, usually achieved by the use of calcineurin inhibitors. The possible relationship between cyclosporine and autoimmune phenomena is supported by several clinical and experimental features.…”

“…We studied HLA class I and II polymorphism by standard complement-dependent microcytotoxicity assays and/or by PCR with sequence-specific primers for the following antigens/alleles: A (1,2,3,11,23,24,25,26,29,30,31,32,33,34,66,68,69,80), B (7,8,13,18,27,35,37,38,39,41,42,44,45,47,48,49,50,51,52,53,55,56,57,58,60,61,62,63,64,65,67,70,73), Cw (1,2,3,4,…”

The Cell Biology of Cytomegalovirus: Implications for Transplantation

“…CMV infection has been associated with humoral and cellular autoimmunity to islet autoantigens and type 1 diabetes in a pancreas recipient. In stem cell recipients, clinical CMV infection and CD13 upregulation on permissive CMV cells may participate in the generation of CD13 autoantibodies (150). Asparagine-glycinearginine binds CD13 (151); future therapies might target CD13 on CMV-infected cells.…”

Autoimmune haemolytic anaemia emerging during Campath treatment in a patient with CD5 negative chronic lymphocytic leukaemia

“…Alternatively, CMV reactivation might have induced the same mechanism and contribute directly to haemolysis. Indeed CMV is known to be associated with autoimmune disorders including AIHA in immune compromised [12] and less commonly in immune competent individuals [13]. CD5 negative CLL generally follows an aggressive course with a median survival similar to those of CD5 positive patients [8].…”