Perforinopathy: A Spectrum of Human Immune Disease Caused by Defective Perforin Delivery or Function

Abstract

Congenital perforin deficiency is considered a rare cause of human immunopathology and immune dysregulation, and classically presents as a fatal illness early in infancy. However, we propose that a group of related disorders in which killer lymphocytes deliver only partially active perforin or a reduced quantum of wild-type perforin to the immune synapse should be considered part of an extended syndrome with overlapping but more variable clinical features. Apart from the many rare mutations scattered over the coding sequences, up to 10% of Caucasians carry the severely hypomorphic PRF1 allele C272 > T (leading to A91V mutation) and the overall prevalence of the homozygous state for A91V is around 1 in 600 individuals. We therefore postulate that the partial loss of perforin function and its clinical consequences may be more common then currently suspected. An acute clinical presentation is infrequent in A91V heterozygous individuals, but we postulate that the partial loss of perforin function may potentially be manifested in childhood or early adulthood as “idiopathic” inflammatory disease, or through increased cancer susceptibility – either hematological malignancy or multiple, independent primary cancers. We suggest the new term “perforinopathy” to signify the common functional endpoints of all the known consequences of perforin deficiency and failure to deliver fully functional perforin.

Missense mutations in the perforin (PRF1) gene as a cause of hereditary cancer predisposition

“…11,17 Whereas, the complete loss of PRF function typically presents in early childhood as FHL2, the subtotal loss of PRF activity causes systemic inflammatory disease that is delayed beyond infancy (as in the index case II-1) or may present as a different immunopathology. 6 In these instances, consistent with Burnet's hypothesis of tumor immune surveillance, 19 reduced cytotoxic lymphocyte activity caused by partial loss of PRF may be expected to predispose to neoplasia, and this is indeed supported by previous studies. [9][10][11][12] It is not clear, however, why these malignancies thus far reported in humans in association with PRF deficiency are predominantly haematological.…”

“…5 However, it is possible that FHL2 represents one extreme of a spectrum of diseases caused by PRF deficiency. 6 Thus, missense mutations causing partial loss of expression or function of PRF are more often associated with later atypical onset FHL2 7 and/ or haematological malignancy. [8][9][10][11][12] It is unknown whether PRF deficiency can predispose to solid tumors, nor has a possible contribution of PRF1 mutations to familial cancer ever been explored.…”

How I treat hemophagocytic lymphohistiocytosis in the adult patient

“…Primary HLH and secondary HLH have historically been considered separate entities; however, these new genetic insights and the observation that primary HLH is often set off by a trigger suggest that there may be more overlap than previously recognized. 49 …”

Molecular mechanisms regulating cytotoxic lymphocyte development and function, and their associations to human diseases

“…Focusing on NK cells, Ham and Billadeau (9) summarize a variety of human immunodeficiency syndromes that affect lymphocyte cytotoxicity, bridging the molecular, and clinical side of this Research Topic. A Hypothesis and Theory article introduces the interesting concept of "perforinopathy" (10). The authors discuss how immune dysregulation and immunopathology are caused by, or related to decreased perforin activity and/or delivery to the target cells, and present compelling evidence that this may be more common cause of human disease than previously assumed.…”