Cytopathology or immunopathology? The puzzle of cytomegalovirus pneumonitis revisited

Various hypotheses have been proposed to explain why cytomegalovirus pneumo nitis (CMV-P) is frequent and severe in bone marrow transplant patients whi le remaining rare and mild in HIV infected patients. One hypothesis suggest s that CMV-P is an immunopathological condition that is common in bone marr ow transplantation (BMT) under the effects of an abnormally regenerating im mune system that reacts against CMV infected lung tissue. Such a hypothesis implicates CD4 T lymphocytes as one of the critical cell populations invol ved in immunopathology and also suggests that this process mould be aborted by CD4 T cell deficiency in HN infection, However, studies correlating the onset of CR;IV-P with lymphocyte reconstitution following BMT have reveale d that CD4 cells are present at very low frequencies in the blood during th e early period after transplantation when most cases of CMV-P occur. Furthe rmore, studies directly investigating bronchoalveolar lavage cell types dur ing episodes of CMV-P in BMT patients have also failed to demonstrate signi ficant CD4 involvement and, instead, have emphasized a predominance of natu ral killer (NK) cells and CD8 cells. These findings serve as the basis for questioning the validity of a CD4-driven immunopathological model of CMV-P in BMT. On the other hand, a variety of experimental and clinical observati ons support the protective role of CMV-specific CD3(+) CD8 T lymphocytes ag ainst CR;IV in both immunocompetent individuals and BMT patients, In a muri ne BMT model, adoptive transfer of syngeneic BM cells was associated with m assive increases in lung CD8 cells which resulted in the resolution rather than the exacerbation of existing CMV-P. In the light of these findings a m ore plausible hypothesis for CMV-P in BMT is that during the early period a fter transplantation adequate protective CD8 responses are absent and an un controlled CMV proliferation is allowed to develop. Once a critical viral l oad is reached a cytokine 'storm' may be triggered in the lung tissue that aggravates direct CMV-associated cytopathic effects. Likely candidates for this process mould include the release of tumour necrosis factor-alpha (TNF -alpha) from alveolar macrophages stimulated by interferon-gamma (IFN-gamma ) released from NK cells that are reconstituted early after BMT.