Ординатура / Офтальмология / Английские материалы / Practical Manual of Intraocular Inflammation_Dick, Okada, Forrester_2008

Figure 4 Activation and polarization of T-cell responses. T cells are activated by receptor-ligand interactions in what is known as the immunological synapse. Antigen is processed by the DC, peptides of which are presented to T cells within the MHC groove on the DC, which is recognized by TCR. For CD4þ T-cell activation, this involves MHC class II molecules. For full T-cell activation, peptide presentation occurs alongside co-stimulation via other receptor-ligand interactions, such as CD28-B7 and CD40L-CD40. Once T-cell activation occurs, their polarization and function are identified by cytokines they release. Abbreviations: DC, dendritic cells; MHC, major histocompatability complex; TCR, T-cell receptor.

presence of naturally occurring regulatory T cells (Treg cells). Over time, there have been many regulatory phenotypes described, some of which are naturally occurring and others that are induced following antigen recognition (Fig. 5) (11).

Irrespective of which triggering event breaks the regulation, antigen-specific CD4þ T cells can initiate disease only after peripheral clonal expansion and probably on further presentation of antigen either in regional drainage lymph nodes or at the target tissue (Fig. 6).

Initiation of autoinflammation is subclinical. Once symptomatic, it is likely that the majority of the responses we see clinically in the eye are nonspecific inflammation and chronic (Fig. 7). There may be additional local cellular and molecular immune regulatory mechanisms also acting to reduce the bystander collateral damage on the background of a reduced but constant antigen-specific response.

Evidence for Autoinflammatory Disease

As we have discussed above, the general view is that PSII is regarded as a CD4þ T cell–mediated disease where activated T cells can be detected in the peripheral blood as well as ocular fluids of patients with uveitis. There is no definitive evidence for autoimmunity, hence, the more accepted term autoinflammatory, where the evidence is compelling in comparison with only circumstantial evidence of true autoimmunity (Table 3). Studies show that in the peripheral blood, there are markers of immune activation, including vascular endothelial

Figure 5 Classes of regulatory T cells. Natural Tr cells develop in the thymus, their TCR repertoire is mainly self-reactive, and the expression of Foxp3þ determines their regulatory function. In human disease IPEX, there are mutations in Foxp3. There is, however, diversity in regulatory cells. Tr1 cells (Foxp3neg) and Th3 cells, which are induced following antigen exposure and regulate as a result of their signature cytokines they generate (IL-10 and TGFb, respectively). Abbreviations: TCR, T-cell receptor; IPEX, immune dysfunction/polyendocrinopathy/enteropathy/ x-linked.

Table 3 Evidence of Immune Activation in Patients with Noninfectious Uveitis

Autoimmunity and T-cell activation in uveitis

. Peripheral T-cell activation (IL-2r, CD69)

. Immune activation upregulation of adhesion molecules and selectins

. Association with HLA-DR15, HLA-DR4

. Tyrosinase-specific CD4+ T cell in VKH

. S-Ag-specific T cell in uveitis

. Clinical response to anti-T-cell agents (e.g., CsA and anti-TAC)

activation, the presence of autoreactive tyrosinase-related protein–specific T cells in VKH as well as S-Ag-specific T-cell responses and S-Ag-specific autoantibodies, particularly, for example, in Birdshot chorioretinopathy. More recently, there is data that supports increased Th17 responses in the peripheral blood of VKH patients as well as other forms of uveitis and scleritis, which, like the interferon-gamma Th1 T-cell counterpart, is IL-2-dependent as the cells’ growth factor (12). We also know that there is a significant association of PSII phenotypes with HLA-major histocompatability complex (HLA-MHC) class II

Figure 6 Activation of an autoinflammatory response. Activated DC traffic to the regional lymph nodes where the DC will present peptides of putative ocular autoantigens (S-antigen, retinoidbinding protein, phosducin, or tyrosinase-related proteins) to T cells, generating activated antigenspecific CD4þ T cells. Antigen-specific CD4þ T cells home back to the eye where further interaction with resident and infiltrating myeloid cells activates macrophages that contribute to the autoinflammatory tissue damage. Abbreviation: DC, dendritic cells.

alleles, implicating CD4þ T-cell activation in the pathogenesis of disease (Table 4) (13). This is particularly so for PSII related with systemic disease, such as VKH, JIA-associated uveitis, tubulointerstitial nephritis and uveitis (TINU), and intermediate uveitis. The association with HLA-DR antigens are similar to that described for other autoinflammatory conditions such as rheumatoid arthritis, inflammatory bowel disease, diabetes mellitus, and multiple sclerosis. The significance of the HLA association between different populations depends on the prevalence of the relevant gene in the population. This is true even for different HLA-DR associations being reported for different populations (e.g., sympathetic ophthalmia with DRB1*0405 in Asians and *0404 in Europeans). Extending the role of genetic influences in autoinflammatory disease, there has been increasing interest in the understanding of Class III MHC genes, or cytokine and chemokine polymorphisms in generating evidence for predicting predisposition, severity, and course of disease. These include polymorphisms in tumor necrosis factor (TNF) and TNF receptor genes, IL-10, interferon-gamma, and chemokines such as

Figure 7 Engaging a non-antigen-specific response contributing to tissue damage. Following initial activation of APC (DC) and then trafficking to lymph node, the early event of antigenspecific T-cell activation and proliferation is with time diluted by the pro-inflammatory cascade. With increasing chronicity of disease, more nonspecific T-cell activation and macrophage activation within the target tissue occurs. Activation of macrophages and other myeloid cells (mast cells, neutrophils) gives rise to the tissue damage we observe clinically, mediated by reactive oxygen species, nitric oxide, and direct cytolytic effect of some of the cytokines generated by both the myeloid and T cells. Abbreviations: APC, antigen-presenting cells; DC, dendritic cells.

Table 4 HLA Associations with Noninfectious Ocular Inflammatory Conditions

Abbreviations: TINU, tubulointerstitial nephritis and uveitis; VKH, Vogt-Koyanagi-Harada syndrome; HLA, human leukocyte antigen.

CXCR1, CXCR2, CCL2, and CCL5 in studies of various cohorts of patients including Behc¸et’s disease, sympathetic ophthalmia, intermediate uveitis, and retinal vasculitis. Although in general, the data is not robust to accurately predict, there is ever increasing evidence supporting the influence genetic polymorphisms have in the severity and course of uveitis. For example, specific mutations can lead

to hypersecretion of cytokines such as mutations in cold autoinflammatory syndrome 1 (CIAS1) gene that encodes cryopyrin and leads to hypersecretion of IL-1 and conditions related to ocular inflammation such as chronic infantile neurological, cutaneous, articular (CINCA) syndrome.

Archetypically, one current concept is that PSII is mediated by Th1 CD4þ T cells, which generate interferon-gamma and require IL-2 as an essential growth factor. Consequently, one can detect evidence of Th1 activation in the peripheral blood, for example, raised serum IL-2 receptor levels, and increased CD69 expression on T cells. More recently, there is evidence for Th17 activation and upregulation of cell numbers in uveitis patients. What is manifest and supports a T cell–driven disease is the response to therapy of specific T-cell calcineurin inhibitors such as cyclosporin or tacrolimus and, most recently, specific IL-2 receptor blockade (anti-TAC).

PRACTICAL CLASSIFICATION FOR MANAGEMENT

Throughout the handbook, we will emphasize a practical view of classifying patients to assist their management and develop schema to follow to assist diagnosis and treatment of sight-threatening disease. The concept follows: examination of patients for both ocular and systemic manifestations of inflammatory disease (and other comorbid disease states), a decision (and this may require support from laboratory and imaging investigation) as to whether PSII is infective or noninfective, and finally, whether the patient has sightthreatening disease or not. This initial clinical assessment determines the appropriate treatment at the outset, which can be modified when further results arrive or changes occur clinically.

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