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Year : 1993  |  Volume : 41  |  Issue : 3  |  Page : 105-106

Current concepts of auto-immune diseases and their therapeutic implications with particular reference to uveitis


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How to cite this article:
Das U N. Current concepts of auto-immune diseases and their therapeutic implications with particular reference to uveitis. Indian J Ophthalmol 1993;41:105-6

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Das U N. Current concepts of auto-immune diseases and their therapeutic implications with particular reference to uveitis. Indian J Ophthalmol [serial online] 1993 [cited 2023 Dec 8];41:105-6. Available from: https://journals.lww.com/ijo/pages/default.aspx/text.asp?1993/41/3/105/25610

In 1934, Duke-Elder [1] expressed the view that most cases of uveitis were due to some ill-defined infective agent, affecting the eye remotely by an allergic mechanism. It is now believed that endogenous uveitis is due to an aberration in immunological mechanism(s), though infection is still believed to play a part in precipitating the disease.

Uveitis is classified as exogenous when it is caused directly by some infective agent (eg. cytomegalo­virus, herpes simplex) or endogenous when it occurs de novo without any obvious inciting agent. However, endogenous uveitis has strong indirect links with infective agents, which are implicated in its pathogenesis. Pathogenetically anterior and posterior uveitis are discrete entities. Fifty-six percent of cases of anterior uveitis are associated with the MHC class I alloantigens, and the disorder is more closely linked with infectious agents such as Klebsiella and Yersinia than is posterior uveitis. However, the contribution of these agents is indirect, by the production of disturbances in immune function. Posterior uveitis is more commonly believed to be autoimmune in origin. MHC class II antigens, particularly HLA DR, are more likely to be involved in this type of uveitis.


Damage to the ocular structures, and thus visual loss is mediated by the inflammatory cellular exudate in uveitis. Cytological studies of aqueous and vitreous humour in acute anterior uveitis have revealed the presence of various subsets of activated T and B-cells. [2],[3] Similar to the mechanisms required to mount an immune response to a foreign antigen, autoimmune responses are initiated by the presentation of an autoantigen by interferon producing MHC class II positive antigen-presenting cells to CD4 T-cells, which then produce lymphokines such as IL-2 (interleukin-2), tumour necrosis factor (TNF) and other cytokines and activate other types of CD4 and CD8 T-cells. These activated cells act as effector cells, either directly (cytotoxic T-cells) or by activating other effector cells such as antibody producing B-cells or antigen-specific activated macrophages.

The interaction between the antigen on the antigen-presenting cells and the CD4 T-cell receptor is highly specific. The adhesion molecules, such as the intercellular adhesion molecule -1 (ICAM-1), which bind to the T-cell ligand leukocyte function antigen-1 (LFA-1) are required to promote the reaction and induce a T-cell signalling event. These adhesion molecules including ICAM-1 are also necessary in the homing of the activated T-cells to the site of inflammation since they are also expressed on activated endothelial cells and promote lymphcocyte/endothelial cell interaction before migration of the cell into the tissues.

Experimental models of uveitis (EAU) can be induced by immunising the animals with a retinal auto­antigen (usually retinal S-antigen or interphotoreceptor retinal binding protein). In this model, CD4 T-cells were observed to accumulate around blood vessels in the retina and choroid during the early phase of the disease. In addition, phagocytic macrophages infiltrate the site of autoimmune attack, the photoreceptor cell. After this initial phase, a wave of CD8 T-cells follows, with increasing numbers of macrophages and polymorphonuclear leukocytes. Differences in the responses to S-antigen, interphotoreceptor retinal binding protein, or other retinal antigens, such as rhodopsin and phosducin, are probably related to the dose of antigen, species and genetic susceptibility. Thus, EAU is a CD4 T-cell mediated disease. There is also evidence to believe that macrophages are of considerable importance in inducing tissue damage and the macrophage is the first cell to appear at the target site, i.e. the photoreceptor cell in EAU. [4]

The homing of antigen-specific T-cells to the site -of inflammation and tissue damage can be related to lymphocyte-endothelial cell adhesion and interaction. Human retinal pigmented epithelial cells, which form one part 'of the blood ocular barrier, constitutively express ICAM-1 and retinal endothelial cells can be induced by gamma-interferon (IFN) to express ICAM-1 antigen on their cell surfaces. Blockade of this molecular response by ICAM-1 specific monoclonal antibodies inhibits adhesion of activated T-lymphocytes and thus can effectively prevent inflammation and possibly, uveitis. Thus, interactions between ICAM-1 and LFA-1 are important in directing lymphocyte traffic during occular immune responses.

In addition, the activated macrophages, T-cells and neutrophils can produce and secrete eicosanoids (prostaglandins and leukotriences), free radicals and various cytokines including ILs, TNF and IFN which have pro-inflammatory actions. [4] These molecules . are not only the inducers of inflammation but can also perpetuate it and pave way for the occurrence of chronic inflammation at a given site. Some of the local factors that may determine the progression and continuation of inflammation include the local concentra­tions of essential fatty acids and the metabolites. In a recent study, we and others have shown that fatty acids such as arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaneoic acid can inhibit T- cell proliferation and block IL-1, IL-2 and TNF secretion by activated human T-cells. [6],[7],[8] Both in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) which can be associated with uveitis and which are also autoimmune diseases, the plasma levels of EPA and other fatty acids were found to be low. [9] Further, the metabolites of EPA and dihomogamma-linolenic acid (DGLA) are known to have anti-inflammatory actions. Thus, in situations wherein EPA, DHA and DGLA levels are low, the T-cell proliferation and TNF, IL-1 and IL-2 production may not be inhibited, so contributing to chronic inflammation as seen in collagen vascular diseases and uveitis.

  Suggested therapeutic strategies in uveitis Top

As is evident from the preceding discussion, efforts made to block the generation of cytokines, free radicals and eicosanoids may he of benefit in the treatment of uveitis. But this is difficult to achieve. One strategy is to suppress T-cell proliferation which generate these pro-inflammatory molecules. This can be done by the use of various immunosuppressive drugs such as cyclosporine, cyclophosphamide, azathiprine, corticosteroids and methotrexate. Since steroids have several unwanted side-effects it is best that they are avoided altogether, if possible. We have been using low dose, oral methotrexate in the treatment of rheumatoid arthritis with good results. With this experience, we tried (in collaboration with Dr. T. P. Das of L.V.Prasad Eye Institute) oral methotrexate in the treatment of uveitis. Majority of these patients have already used or were using corticosteroids (both oral and local) at the time of inclusion in the study with little or no improvement. In about 50 patients studied so far, almost 70-80% of these patients showed significant clinical improvement with no side effects. The dose of methotrexate used was 7.5 mg/wk.

Another strategy could be intravenous cyclophosphamide pulse therapy as practised in the treatment of SLE. Possible use of specific monoclonal antibodies against various adhesion molecules need to be explored.

In a recent study, [9]it was observed that oral supplementation of type II collagen can improve RA. It was noted that oral type II collagen activates type II collagen specific CD8 cells in gut lymphoid tissue. When these cells, distributed by blood, reach the inflammed joint they release anti-inflammatory cytokines. If this is true, oral supplementation of retinal S-antigen may constitute a new form of therapy for uveitis.

  References Top

Duke-Elder S. The prognosis of iritis and iridocyclitis. Lancet. ii: 100-102, 1934.  Back to cited text no. 1
Kaplan HJ, Waldrep CJ, Nicholson JK, and Gordon D. Immunologic analysis of intraocular mononuclear cell infiltrates in uveitis. Arch Ophthalmol. 102: 572-575, 1984.  Back to cited text no. 2
Deschennes J, Char DH, and Kalita S. Activated T lymphocytes in uveitis. Br J Ophthalmol. 72: 83-87, 1988.  Back to cited text no. 3
Forrester JV, Liversidge J, Dua HS, Towler H, and McMenamin PG. Comparision of clinical and experi­mental uveitis. Curr Eye Res. 9:75-84, 1990.  Back to cited text no. 4
Das UN. Interaction(s) between essential fatty acids, eicosanoids, cytokines, growth factors and free radi­cals. Relevance to new therapeutic strategies in rheu­matoid arthritis and other collagen vascular diseases. Prostaglandins Leukotrienes and Essential Fatty Acids. 44:201-210, 1991.  Back to cited text no. 5
Santoli D, Phillips PD, Colt TC, and Zurier RB. Sup­pression of interleukin-2 dependent human T cell growth in vitro by prostaglandin E (PGE) and their precursor fatty acids. J Clin Invest. 85: 424-432, 1990.  Back to cited text no. 6
Sravan Kumar G, Das UN, Vijay Kumar K, Madhavi N, Das NP, and Tan BKH. Effect of n-6 and n-3 fatty acids on the proliferation and secretion of TNF and IL-2 by human lymphocytes in vitro. Nutrition Res. 12: 815-823, 1992.  Back to cited text no. 7
Das UN, Ramesh G, Sravan Kumar G, et al. Free radicals, lipid peroxidation and essential fatty acids in patients with pneumonia, septicemia, and collagen vascular diseases. J Nutritional Med. 3: 117-128, 1992.  Back to cited text no. 8
Trentham DE, Dynesins-Trentham RA, Orav EJ et al. Effects of oral administration of type II collagen on rheumatoid arthritis. Science. 261: 1727-1730, 1993.  Back to cited text no. 9


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