Autoantibodies against cytokines: Back to human genetics

ArticleinBlood 121(8):1246-7 · February 2013with20 Reads
DOI: 10.1182/blood-2013-01-474213 · Source: PubMed
In this issue of Blood, Chi et al have discovered that the occurrence of autoantibodies against IFN-γ, which trigger mycobacterial diseases and mimic inborn errors of IFN-γ immunity, is genetically determined. 1.
    • "The most consistent results obtained with HLA variants have been those for leprosy (Zhang et al. 2009a) and, particularly, for HIV infection (Goulder and Watkins 2008; Leslie et al. 2010), with some HLA class I alleles being associated with relatively successful control of viral replication and slow disease progression (Migueles et al. 2000; Kiepiela et al. 2004), and others being associated with relatively ineffective control of viral replication and rapid disease progression (Carrington et al. 1999; Kiepiela et al. 2004). Finally, a recent study reported that autoantibodies against IFN-g conferring a predisposition to mycobacterial infections and mimicking MSMD (Puel and Casanova 2013) are strongly associated with two linked HLA class II alleles (Chi et al. 2013). "
    [Show abstract] [Hide abstract] ABSTRACT: Human genetic studies are rarely conducted for immunological purposes. Instead, they are typically driven by medical and evolutionary goals, such as understanding the predisposition or resistance to infectious or inflammatory diseases, the pathogenesis of such diseases, and human evolution in the context of the long-standing relationships between humans and their commensal and environmental microbes. However, the dissection of these experiments of Nature has also led to major immunological advances. In this review, we draw on some of the immunological lessons learned in the three branches of human molecular genetics most relevant to immunology: clinical genetics, epidemiological genetics, and evolutionary genetics. We argue that human genetics has become a new frontier not only for timely studies of specific features of human immunity, but also for defining general principles of immunity. These studies teach us about immunity as it occurs under "natural" conditions, through the transition from the almost complete wilderness that existed worldwide until about a century ago to the current unevenly distributed medically shaped environment. Hygiene, vaccines, antibiotics, and surgery have considerably decreased the burden of infection, but these interventions have been available only recently, so have yet to have a major impact on patterns of genomic diversity, making it possible to carry out unbiased evolutionary studies at the population level. Clinical genetic studies of childhood phenotypes have not been blurred by modern medicine either. Instead, medical advances have actually facilitated such studies, by making it possible for children with life-threatening infections to survive. In addition, the prevention and treatment of infectious diseases have increased life expectancy at birth from ∼20 yr to ∼80 yr, providing unique opportunities to study the genetic basis of immunological phenomena against which there is no natural counterselection, such as reactivation and secondary infectious diseases and breakdown of self-tolerance manifesting as autoimmunity, in populations of adult and aging patients. Recently developed deep sequencing and stem cell technologies are of unprecedented power, and their application to human genetics is opening up exciting and timely possibilities for young immunologists seeking uncharted waters to explore.
    Article · Oct 2013
  • [Show abstract] [Hide abstract] ABSTRACT: We review the primary immunodeficiencies (PIDs) underlying an increasing variety of superficial and invasive fungal infections. We also stress that the occurrence of such fungal infections should lead physicians to search for the corresponding single-gene inborn errors of immunity. Finally, we suggest that other fungal infections may also result from hitherto unknown inborn errors of immunity, at least in some patients with no known risk factors. An increasing number of PIDs are being shown to underlie fungal infectious diseases in children and young adults. Inborn errors of the phagocyte NADPH oxidase complex (chronic granulomatous disease), severe congenital neutropenia (SCN) and leukocyte adhesion deficiency type I confer a predisposition to invasive aspergillosis and candidiasis. More rarely, inborn errors of interferon-γ immunity underlie endemic mycoses. Inborn errors of interleukin-17 immunity have recently been shown to underlie chronic mucocutaneous candidiasis (CMC), while inborn errors of caspase recruitment domain-containing protein 9 (CARD9) immunity underlie deep dermatophytosis and invasive candidiasis. CMC, invasive candidiasis, invasive aspergillosis, deep dermatophytosis, pneumocystosis, and endemic mycoses can all be caused by PIDs. Each type of infection is highly suggestive of a specific type of PID. In the absence of overt risk factors, single-gene inborn errors of immunity should be sought in children and young adults with these and other fungal diseases.
    Article · Dec 2013
  • [Show abstract] [Hide abstract] ABSTRACT: Cytokines regulate many aspects of cell growth and differentiation and play pivotal roles in the orchestration of immune defence against invading pathogens. Though 'self' proteins, they are potentially immunogenic and can give rise to anti-cytokine autoantibodies (aCA). The main foci of the article are a critical summary of the various methodologies applied for detecting and measuring aCA and a broad review of studies of the occurrence, characterization and clinical relevance of aCA in normal healthy individuals, patients with autoimmune diseases or microbial infections and aCA in patients whose disease is treated with recombinant cytokine products. The need for technical and methodological improvement of assays, including validation and standardization, together with approaches to harmonize calculation and reporting of results is also discussed.
    Article · Jun 2014
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