Reconciling Mouse and Human Immunology at the Altar of Genetics

Abstract

Immunity to infection has been extensively studied in humans and mice bearing naturally occurring or experimentally introduced germline mutations. Mouse studies are sometimes neglected by human immunologists, on the basis that mice are not humans and the infections studied are experimental and not natural. Conversely, human studies are sometimes neglected by mouse immunologists, on the basis of the uncontrolled conditions of study and small numbers of patients. However, both sides would agree that the infectious phenotypes of patients with inborn errors of immunity often differ from those of the corresponding mutant mice. Why is that? We argue that this important question is best addressed by revisiting and reinterpreting the findings of both mouse and human studies from a genetic perspective. Greater caution is required for reverse-genetics studies than for forward-genetics studies, but genetic analysis is sufficiently strong to define the studies likely to stand the test of time. Genetically robust mouse and human studies can provide invaluable complementary insights into the mechanisms of immunity to infection common and specific to these two species. Expected final online publication date for the Annual Review of Immunology, Volume 41 is April 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

The immunopathological landscape of human pre-TCRα deficiency: From rare to common variants

“…As in humans, we observed a progressive increase in mouse blood αβ T cell counts with age, driven by memory cell accumulation. These findings highlight the need for caution when extrapolating phenotypes from mutant mice, which are often studied at a young age and in a narrow range of experimental conditions, to humans ( 39 , 40 ). They also suggest that it can be productive to revisit mouse phenotypes on the basis of human studies.…”

Encephalitis and poor neuronal death–mediated control of herpes simplex virus in human inherited RIPK3 deficiency

“…By contrast, the absence of obvious leukocytic abnormalities in the RIPK3-deficient patient is consistent with the absence of serious infections other than HSE in this patient until the age of 24 years. Future studies searching for inborn errors of RIPK1, RIPK3, and related molecules in patients with HSE and other diseases will improve our understanding of RIPK1 and RIPK3 biology in natural conditions (86)(87)(88)(89).…”

The TRIM37 variants in Mulibrey nanism patients paralyze follicular helper T cell differentiation

“…It is likely that the specific TRIM37 variants present in this case encoded mutated TRIM37 protein, altering its functions in T cells. Another possibility is that our inbred mice are maintained in specific pathogen-free barrier animal facilities, while the diverse human living environment, especially the presence of pathogens, is also important to modulate gene effects 52 .…”