Immunological loss-of-function due to genetic gain-of-function in humans: autosomal dominance of the third kind

Abstract

All the human primary immunodeficiencies (PIDs) recognized as such in the 1950s were Mendelian traits and, whether autosomal or X-linked, displayed recessive inheritance. The first autosomal dominant (AD) PID, hereditary angioedema, was recognized in 1963. However, since the first identification of autosomal recessive (AR), X-linked recessive (XR) and AD PID-causing genes in 1985 (ADA; severe combined immunodeficiency), 1986 (CYBB, chronic granulomatous disease) and 1989 (SERPING1; hereditary angioedema), respectively, the number of genetically defined AD PIDs has increased more rapidly than that of any other type of PID. AD PIDs now account for 61 of the 260 known conditions (23%). All known AR PIDs are caused by alleles with some loss-of-function (LOF). A single XR PID is caused by gain-of-function (GOF) mutations (WASP-related neutropenia, 2001). In contrast, only 44 of 61 AD defects are caused by LOF alleles, which exert dominance by haploinsufficiency or negative dominance. Since 2003, up to 17 AD disorders of the third kind, due to GOF alleles, have been described. Remarkably, six of the 17 genes concerned also harbor monoallelic (STAT3), biallelic (C3, CFB, CARD11, PIK3R1) or both monoallelic and biallelic (STAT1) LOF alleles in patients with other clinical phenotypes. Most heterozygous GOF alleles result in auto-inflammation, auto-immunity, or both, with a wide range of immunological and clinical forms. Some also underlie infections and, fewer, allergies, by impairing or enhancing immunity to non-self. Malignancies are also rare. The enormous diversity of immunological and clinical phenotypes is thought provoking and mirrors the diversity and pleiotropy of the underlying genotypes. These experiments of nature provide a unique insight into the quantitative regulation of human immunity.

Figure 1

Clinical manifestation of 17 AD GOF PIDs. Infections are defined as conditions caused by infectious agents: viruses, bacteria, fungi or parasites. Allergies are defined as conditions caused by hyperreactivity to environmental triggers, including, in particular, but not exclusively, T-cell and/or B-cell antigens. Autoimmunity is defined as disease caused by self antigen-reactive T cells and/or B cells. Malignancy is defined by the uncontrolled proliferation of cells, such as leukemia or lymphoma. Other clinical diseases with immunological mechanisms are collectively referred to as autoinflammation, comprising at least the six categories proposed by Dan Kastner [180], and including a growing number of syndromes and conditions. We arbitrarily excluded inborn errors of osteoclasts from this classification (see section ‘Introduction’). Each of these five categories is highly diverse clinically and immunologically. Several AD PIDs by GOF display features from two or more of these four broad types of manifestations. We do not use the term ‘immune dysregulation’, for which no precise definition is available. We also refrain from using the term ‘immunodeficiency’, which may be ambiguous (more than the term PID, the broad signification of which is now widely accepted), referring sometimes, but not always, to an immunological deficit underlying infections and excluding autoimmunity, autoinflammation, allergy, and malignancy.