Elsevier

Journal of Autoimmunity

Volume 35, Issue 3, November 2010, Pages 199-205
Journal of Autoimmunity

The odd couple: A fresh look at autoimmunity and immunodeficiency

https://doi.org/10.1016/j.jaut.2010.06.008Get rights and content

Abstract

The paradoxical relationship between immunodeficiency (under-responsiveness) and autoimmunity (over-responsiveness) affecting the immune system was debated at the Fourth AARDA Colloquium on cross-disciplinary issues in autoimmunity. Immunodeficiency disease and autoimmune disease, far from being mutually exclusive, share profound dysregulation of the immune system. Among the most keenly discussed issues were: i) the remarkably high number of molecularly identified primary immunodeficiencies with autoimmune expressions; ii) the homeostasis of immune function such that deficiency in any one given compartment can result in over activity in the same or another compartment; iii) whilst some immune deficiency states are essentially monogenic, each of them can exhibit striking variability in autoimmune outcome, indicative of epigenetic or environmental influences on phenotypic expression; iv) innate immunity, particularly complement defects, as well as adaptive immunity, is complicit in the immunodeficiency-autoimmunity axis; v) features of certain of the disorders discussed at the meeting forced a reappraisal of what actually is meant by ‘autoimmune disease’. It was concluded that genes that determine inherited immunodeficiencies, hitherto rather neglected by autoimmunologists, compel attention to consideration of molecular genetic anomalies critical for emergence of autoimmune disease in humans and animals.

Introduction

A Colloquium bridging scientific and clinical disciplines was held in Baltimore in November 2009 to appraise the seemingly paradoxical relationship between immunodeficiency and autoimmunity. The goals included identification of critical research areas that represent under explored or unmet needs, and the discussions presented an opportunity for molecular biologists, geneticists, hematologists, infectious disease specialists and immunologists to expand investigations into the manner in which the immune system is regulated and how self-tolerance is established and maintained. This Colloquium, the fourth in an ongoing series [1], [2], [3], was sponsored by the American Autoimmune Related Diseases Association (AARDA), a nonprofit health agency focused on cross-disciplinary issues in autoimmunity. As with prior Colloquia, this gathering encouraged scientists and clinicians to develop a common lexicon in describing cellular and molecular pathways towards immunoregulation, and identifying features and outcomes of immune disorders that impinge on different clinical disciplines. It might appear that immunodeficiency is an under response, and autoimmunity an over response of the immune system, but immunodeficiency diseases and autoimmune diseases are far from being mutually exclusive: both represent profound dysregulation of the immune system with multisystem expressions due to impaired function of one or more of the cell types or soluble mediators required for the normal immune response.

New opportunities to study genetic mechanisms have recently emerged in clinical investigations on the connection of particular T cell deficiencies, B cell deficiencies, and defects in the innate immune system with the occurrence of autoimmune disease. Moreover, some of these disorders are reproducible in animal models, providing additional opportunities to study the genetic basis and molecular mechanisms underlying both autoimmunity and immunodeficiency.

Section snippets

Objectives of the meeting

The objectives were set out as follows:

  • 1.

    to provide the most up to date listing of recognized immunodeficiency disorders;

  • 2.

    to place these disorders within a framework to assist their recognition and study;

  • 3.

    to indicate which primary immunodeficiency disorders are associated with autoimmune features;

  • 4.

    to provide deeper insight into the kind of autoimmune features that are seen in immunodeficiency diseases.

  • 5.

    to identify common mechanisms that help to explain both types of diseases.

Magnitude and diversity of the association of immunodeficiency disease and autoimmunity

An overview of immunodeficiency diseases, with notation of autoimmune features was based upon the International Union of Immunological Societies (IUIS) Classification of Primary Immunodeficiency Diseases, 2009 (R. Michael Blaese, Immune Deficiency Foundation; Harry Schroeder, University of Alabama, Birmingham, AL) [4]. Attendees at the Colloquium noted the surprisingly large number of primary immunodeficiency diseases already molecularly characterized in which there is recognized one or another

Evolutionary and phylogenetic aspects

A review of the evolution of the adaptive immune system from its innate immune origins (Max Cooper, Emory University, Atlanta, GA) emphasized that normally in vertebrates there is a finely balanced interaction between the innate and the adaptive immune systems. Regulation of this balance is required for development of a well-ordered immune response, and disturbance can be a predecessor of autoimmunity. Based on studies on the sea lamprey [5], representative of jawless vertebrates, the

Recessive monogenic immunodeficiencies

The T-cell- dependent monogenic primary immunodeficiency diseases are the best understood at the genetic level, in part due to close experimental models in mice resulting from inbreeding or gene knockout. The classic examples are autoimmune lymphoproliferative syndrome (ALPS) and autoimmune polyendocrinopathy-candidiasis-ectodermal dysplasia (APECED, also called autoimmune polyendocrine syndrome type 1 (APS-1)). Together with these is usually included the syndrome of immune dysregulation,

The B-cell repertoire

In general, deficiencies and gene variants involving T cells are better understood than B cell deficiencies in terms of defined associations with autoimmune disease. A deficient immunologic repertoire may result in diminished immunocompetence. Thus B cell homeostatic mechanisms can allow the survival of autoreactive cells, so permitting pathogenic autoreactive B cells to enter the repertoire. It may also allow the induction of a less focused, lower affinity response to antigen due to cells with

Complement (C′) deficiencies

Inherited complement deficiencies predispose to autoimmune rheumatic diseases and angioedema as well to susceptibility to infections (Jerry Winkelstein, Johns Hopkins University, Baltimore, MD) [33]. Since there is linkage disequilibrium of complement genes with MHC genes, there can be coinheritance of genes for immunodeficiency and for autoimmune disease. Inheritance of C′ deficiencies is autosomal recessive, and usually heterozygous. The gene variants can involve any of the components of the

Conclusions and recommendations

Understanding the co-occurrence of infection and autoimmune disease presents major challenges. Strategies for further investigation have a very high potential for novel research and improved management of patients, including the following topics and questions. We here present relevant observations emanating from the meeting (bold) and suggestions for investigations (italics).

  • It is now well-established that immunodeficiency diseases and autoimmune diseases share genes in common

    • More precise gene

Editor's note

This Conference Report appears in a special issue of the Journal of Autoimmunity published to acknowledge the prolific contributions of Dr. Harry Moutsopoulos to advances in autoimmunity. We add our particular thanks and congratulations. We note in this issue the broad range of topics which focus on loss of tolerance, and the wide diversity of relevant items including the relationships between immunodeficiency and autoimmunity. This is one of several issues which focus on the contributions of

Acknowledgments

The Colloquium was organized by the American Autoimmune Related Diseases Association and co-sponsored by the Johns Hopkins Center for Autoimmune Disease Research and the Immune Deficiency Foundation, with financial support from Genentech, Talecris Biotherapeutics, Centocor, Roche and the National Institute of Allergy and Infectious Diseases/National Institutes of Health.

References (49)

Cited by (0)

View full text