Comment on Clementi et al, page 4424

Perforin mutations may predispose some individuals to lymphoma, supporting the concept that key immune molecules may act as extrinsic tumor suppressors.

In an exciting development, Clementi and colleagues have found that a proportion of patients with Hodgkin or non-Hodgkin lymphoma and displaying at least some of the common manifestations of hemophagocytic lymphohistiocytosis (HLH) harbor mono (4/29) or biallelic (4/29) mutations of their perforin genes. Perforin is a unique cytolytic protein expressed in cytotoxic lymphocytes, including natural killer (NK) cells and various cytotoxic T-cell subsets, where it is indispensable for lymphocyte granule-mediated death of target cells.1  Perforin-deficient mice have severe defects of cell-mediated immune surveillance of pathogens and transformed cells,1  and most (approximately 60%) develop aggressive B-cell lymphoma.2  At first glance, the study by Clementi and colleagues provides a possible link between perforin mutations in humans and failure of immune surveillance to prevent lymphoma development and growth.

In humans, biallelic mutations of the perforin gene, causing either complete lack or severe deficiency of the encoded protein, have been found in approximately 60% of familial HLH patients.3  HLH is a life-threatening disease of early childhood, associated with profound immune derangement and the clinical syndrome of fever, hepatosplenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, and often, neurological dysfunction. The underlying trigger for disease is a failure of perforin-mediated cytotoxicity in the face of an immune challenge or disturbance that remains poorly characterized in humans. Interestingly, perforin-deficient mice reared in specific pathogen–free conditions do not frequently develop HLH, although they do develop a disease mimicking HLH when infected with the lymphocytic choriomeningitis virus (LCMV).4 

The study by Clementi et al is preliminary and a much larger cohort of patients with Hodgkin and other lymphomas need to be screened to confirm the initial findings. If validated, the study also raises the surprising finding that a single normal perforin allele is insufficient to prevent an HLH-like illness. Classically, HLH is considered an autosomal recessive disorder, and parents of affected children (“carriers”) remain healthy. Recently, it has been shown that the majority of HLH-associated missense mutations resulted either in the complete loss or a dramatic reduction in cytolytic activity of perforin.5  With respect to perforin polymorphisms, the epidemiological, clinical, and in vitro reports strongly suggested that N252S was a neutral polymorphism. By contrast, the effect of perforin polymorphism A91V is yet to be fully understood. Two recent studies both indicated that A91V polymorphism affected the stability and, consequently, reduced the lytic activity of perforin by approximately 50%.5,6  The recent results strongly suggest that the combination of A91V and a detrimental mutation in the second allele may, at the very least, predispose an individual to HLH and/or significantly affect their immune surveillance. There is also a theoretical possibility that A91V homozygous individuals may be predisposed to HLH or lymphomagenesis. However, heterozygotes (with the wild-type second allele) may be significantly affected only in an unlikely event of the dominant-negative effect of A91V polymorphism, and this possibility is yet to be addressed experimentally.

It remains unclear what additional factors might contribute to lymphoma development in the patients with monoallelic mutations in the present study. Notably, one of the patients harbored a mutation of the Fas gene, raising the possibility that additional immune defects might cooperatively bring about disease when perforin expression is less than optimal. Indeed, at least 3 loci other than the perforin gene have been associated with HLH-like syndromes, indicating that an alternative explanation for disease must exist in heterozygote patients reported by Clementi et al. Clementi et al also show that some of the lymphomas arising in humans with biallelic perforin mutations are of T-cell origin. This is in distinct contrast to the B-cell lymphomas and plasmacytomas developing spontaneously in perforin-deficient or FasL mutant mice.2,7  Lymphomas derived from perforin-deficient mice are uniformly major histocompatibility complex (MHC) class I positive and express abundant costimulatory molecules, suggesting a lack of immune selection pressure. It will now be of great interest and importance to characterize the disease course and lymphomas arising in HLH patients in greater detail, since this cohort may be important in defining the relationship between immune dysregulation and failed immune surveillance in humans. ▪

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