Interplay between innate and adaptive immunity in the development of non-infectious uveitis

https://doi.org/10.1016/j.preteyeres.2011.11.004Get rights and content

Abstract

In vertebrates, the innate and adaptive immune systems have evolved seamlessly to protect the host by rapidly responding to danger signals, eliminating pathogens and creating immunological memory as well as immunological tolerance to self. The innate immune system harnesses receptors that recognize conserved pathogen patterns and alongside the more specific recognition systems and memory of adaptive immunity, their interplay is evidenced by respective roles during generation and regulation of immune responses. The hallmark of adaptive immunity which requires engagement of innate immunity is an ability to discriminate between self and non-self (and eventually between pathogen and symbiont) as well as peripheral control mechanisms maintaining immunological health and appropriate responses. Loss of control mechanisms and/or regulation of either the adaptive or the innate immune system lead to autoimmunity and autoinflammation respectively. Although autoimmune pathways have been largely studied to date in the context of development of non-infectious intraocular inflammation, the recruitment and activation of innate immunity is required for full expression of the varied phenotypes of non-infectious uveitis. Since autoimmunity and autoinflammation implicate different molecular pathways, even though some convergence occurs, increasing our understanding of their respective roles in the development of uveitis will highlight treatment targets and influence our understanding of immune mechanisms operative in other retinal diseases. Herein, we extrapolate from the basic mechanisms of activation and control of innate and adaptive immunity to how autoinflammatory and autoimmune pathways contribute to disease development in non-infectious uveitis patients.

Introduction

“Nothing in biology makes sense except in the light of evolution”. This citation of Theodosius Dobzhansky is germane to immunity, inflammation and the pathogenesis and therapeutic targets in ocular inflammatory diseases. In this context, our immune system has developed alongside the diversity of life forms and biological organisms. Maintaining organ and tissue function is dependent upon co-existing with a large genomic array of microbial commensals, whilst concomitantly retaining the capability of responding to pathogenic microbes (Lee and Mazmanian, 2010). For example, early life colonization by bacteria generates host–microbe relationships that do not result in disease – immune tolerance. The corollary is that the majority of host–bacterial interaction is symbiotic and actively contribute to overall homeostasis (Fig. 1) (Casadevall and Pirofski, 2000). Both innate and adaptive immune mechanisms govern such capability. However, a risk of the adaptive immunity is an abnormal response against self protein, a potential requisite to the development of autoimmunity. With respect to the fact that adaptive and innate immunity rely on, at least initially, different molecular mechanisms, their associated diseases, respectively autoimmunity and autoinflammation, arguably also remain distinct. Whereas with reference to ocular disease, the pathways leading to autoimmunity have been most studied where although it remains largely conjecture as to a potential autoantigen (see Section 5), the prominence of the recruitment and activation of innate immunity is increasingly recognized and moreover is arguably requisite for full expression of phenotypes of non-infectious uveitis we observe, and certainly experimentally. To back up such experimental findings clinically, a common occurrence during relapses of uveitis (although not exclusive), is the presence of non-ocular infection, even if not manifest clinically. In this review, we highlight the basic principles of adaptive and innate immunity and how immune mechanisms (autoimmunity versus autoinflammation) contribute to disease development in non-infectious uveitis patients.

Section snippets

Definition of non-infectious uveitis

Currently we define uveitic disorders purely on their clinical phenotype. This classification is undergoing further refinement involving consensus opinion, which is undoubtedly appropriate for clinical outcome studies and clinical trials, but does not fully acknowledge either commonality or diversity of immunopathogenesis (Jabs et al., 2005). Arguably and pre-emptively, we classify clinically intraocular inflammation as either infectious, where there is an obvious infectious aetiology, for

Innate immunity

An innate immune system provides an immediate host immune response to infectious agents and relies on the expression of germline-encoded receptors for their detection. Those receptors recognize microbial-specific molecular patterns (pathogen associated molecular patterns, PAMPs), generally motifs shared by large groups of microorganisms. This clearly makes sense in an evolutionary perspective, since those molecular structures are essential for the survival of microbes and are thus less likely

Autoinflammation and experimental uveitis

A variety of circumstantial observations suggests that the innate immune system is very important in the development of uveitis. These observations include: 1) Most eye tissues (cornea, uvea and retina) expresses TLRs (Chang et al., 2006). NOD1 and NOD2 are also strongly expressed (Rosenzweig et al., 2008, 2009). Accordingly, a variety of synthetic TLR agonists will induce cytokine synthesis and uveitis when injected locally in a mouse eye (Allensworth et al., in press). The prototypic

Evidence supporting the role of autoreactive lymphocytes activation in non-infectious uveitis

Supporting an autoimmune aetiology for non-infectious uveitis, various groups have demonstrated that T lymphocytes from patients with uveitis proliferate in response to retinal antigens, although and perhaps not surprisingly retinal specific autoreactive lymphocytes are also found in the circulation of unaffected individuals (Hirose et al., 1988; Nussenblatt et al., 1980; Opremcak et al., 1991; Yamamoto et al., 1993). Those seminal data have been confirmed by more recent studies which support

Conclusion

Non-infectious uveitis is frequently referred as autoimmune. However, experimentally, non-infectious uveitis requires concomitant and initial activation of innate immunity prior to generation of specific T cell responses. Therefore, clinically, one notion is that even in autoimmune models there is a requisite for both innate immunity (autoinflammation) as well as autoimmunity (antigen-specific T cell mediated) to generate full clinical expression of disease. Genetic and immunological data

Acknowledgements

François Willermain is supported by the Fonds de la recherche en Ophthalmologie (FRO), the asbl Vésale, and grants from the FNRS.

JTR is supported by NIH grants EY019020, EY013093, and EY019604, as well as Research to Prevent Blindness, Fight for Sight, Oregon Clinical Trial Research Institute, William C. Kuzell Foundation, William and Mary Bauman Foundation, and Stan and Madelle Rosenfeld Family Trust.

ADD is supported from grants from National Eye Research Centre, Underwood Trust, Dunhill

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