Digenic Inheritance: Evidence and Gaps in Hemophagocytic Lymphohistiocytosis.

Erica A Steen,Michelle L Hermiston,Lauren K Meyer,Kim E Nichols

doi:10.3389/fimmu.2021.777851

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory disorder characterized by the inability to properly terminate an immune response. Familial HLH (FHLH) and related immune dysregulation syndromes are associated with mutations in the genes PRF1, UNC13D, STX11, STXBP2, LYST, AP3B1, and RAB27A, all of which are required for the assembly, exocytosis, and function of cytotoxic granules within CD8+ T cells and natural killer (NK) cells. Loss-of-function mutations in these genes render the cytotoxicity pathway ineffective, thereby failing to eradicate immune stimuli, such as infectious pathogens or malignant cells. The resulting persistent immune system stimulation drives hypercytokinemia, ultimately leading to severe tissue inflammation and end-organ damage. Traditionally, a diagnosis of FHLH requires the identification of biallelic loss-of-function mutations in one of these degranulation pathway genes. However, this narrow definition fails to encompass patients with other genetic mechanisms underlying degranulation pathway dysfunction. In particular, mounting clinical evidence supports a potential digenic mode of inheritance of FHLH in which single loss-of-function mutations in two different degranulation pathway genes cooperate to impair pathway activity. Here, we review the functions of the FHLH-associated genes within the degranulation pathway and summarize clinical evidence supporting a model in which cumulative defects along this mechanistic pathway may underlie HLH.

Highlights

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome mediated by an ineffective yet hyperactive immune response
They proposed a hierarchy of degranulation pathway genes, with mutations in Ap3b1 conferring the mildest phenotype followed by Lyst, Stx11, Rab27a, and Prf1
We review the consequences of LOF mutations in genes encoding several key components of the lymphocyte degranulation pathway, providing a mechanistic basis for interpreting the clinical significance of variants in one or more of these genes

Summary

INTRODUCTION

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome mediated by an ineffective yet hyperactive immune response. Studies using fibroblasts [20], CTLs [21], and NK cells [22] have consistently demonstrated increased mis-localization of lysosomal proteins to the plasma membrane in cells from patients with HPS2 Following their transport along microtubule pathways to the IS, CGs must dock at the plasma membrane and undergo a priming step prior to their fusion with the membrane and subsequent exocytosis of their contents. As in CHS and HPS2, patients with GS2 present with albinism, neurologic sequelae, and immune dysregulation frequently associated with the development of HLH [23] In regards to the latter, CTLs from patients with GS2 produce CGs with appropriate contents, but these granules are unable to be released via exocytosis, correlating with impaired cytotoxicity [24]. This releases endosomal contents, thereby exposing the target cell cytoplasm to apoptosis-inducing granzymes [41]

A THRESHOLD MODEL OF GENETIC PREDISPOSITION TO HLH

Findings

CONCLUDING REMARKS AND FUTURE DIRECTIONS