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

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.

Figure 1. Host-microbe interactions

Infection can be defined as the acquisition of a microbe by a host (Casadevall and Pirofski, 2000). Most frequently, microbial colonization occurs without ill effect and indeed then contributes to benefit for the host.

Figure 2. PAMPs receptors and their signaling pathways

The cell detects the presence of microbes via PAMPs receptors. Toll-like receptors (TLR) and C-type lectins (not depicted) are expressed on plasma membranes and endosomes while RNA and DNA sensors (not depicted) are present in the cytoplasm. TLR stimulation activates NF-kB and MAPK pathways driving proinflammatory cytokines cascades. Transcription of members of the interferon regulatory factor (IRF) is also central features of this series of receptors. IRF have DNA binding domains and in part activates the transcription of type I interferons as well as other interferon induced genes. Intracellular pathogens are also detected by NOD-like receptors. Upon activation, NOD1 and NOD2 oligomerise and activate the NF-kB and MAPK pathways. Activation of NLRP induces the formation of large scaffolds of proteins, called inflammasomes, which will activate caspase-1 and promote the maturation (and secretion) of interleukin-1beta (IL-1b) and IL-18.

Figure 3. Human iris and retina synthesize IL-8 in response to LPS

Human iris or retina explants (cultured from a 6 mm punch biopsy) were stimulated with the indicated concentrations of LPS (purified from E. Coli 0111:B4 and purchased from Sigma Chemicals). IL-8 production in the supernatant was quantified by ELISA at 24 h post stimulation. Data are represented as mean + s.e.m. of 2 different eyes performed in triplicates. Experiment has been repeated 3 individual times.

Figure 4. Chronic urticaria in a child with CINCA syndrome

Figure 5. Swollen optic disc in a child with CINCA syndrome

a. Before treatment with anti-IL1 inhibitors b. After treatment with anti-IL1 inhibitors

Figure 5. Swollen optic disc in a child with CINCA syndrome

a. Before treatment with anti-IL1 inhibitors b. After treatment with anti-IL1 inhibitors

Figure 6. Induction of uveitis by oral immunization

Lewis rats were fed once with 1 mg of either protein (S-Ag: retinal S-Antigen; Casein: bovine aS1 and aS2 casein) or peptide (PDSAg: aa 342-354 from S-Ag; Cas: aa 73-84 from bovine aS2 casein; Rota: aa 501-602 from rotavirus outer capsid protein vp4), or 0,5ml fat-reduced bovine milk, all mixed with 10 mg Cholera toxin (CTX), feeding CTX alone was used as a control. Uveitis was determined by histology of rat eyes. N = number of eyes. Purified casein contains less than 20% aS2 casein (180 mg aS2 casein in 1 mg casein), and 0,5 ml bovine milk contains about 1,4 mg aS2 casein.