Uveitis is classified as noninfectious when there is no known active systemic or intraocular infection, and the pathogenesis is presumed to be immune mediated [1–4]. Both autoimmune and autoinflammatory mechanisms are involved in the development of noninfectious uveitis [1–3, 5].

However, infectious triggers are increasingly recognized in the etiopathogenesis of immune-mediated inflammatory disorders in general and immune-mediated uveitis in particular [1, 2, 6–8].

A constant interplay between the innate and adaptive immune systems is required for maximum protection of the organism against invading pathogens while maintaining immunological tolerance to self as well as to the commensal microbiota that mostly have a symbiotic relationship with the host. Innate and adaptive arms of the immune system are thought to play a predominant role in the autoinflammatory and autoimmune mechanisms, respectively [6, 9, 10].

The innate immune system provides a fast and robust first-line defense against a wide range of pathogens that constitutively express pathogen-associated molecular patterns (PAMPs), including lipopolysaccharide (LPS), peptidoglycan, bacterial DNA/heat shock proteins (HSP), and viral DNA/RNA [1, 6]. Effector cells of the innate immune system include dendritic cells, monocytes/macrophages, natural killer (NK) cells, and neutrophils. Germline-encoded pattern recognition receptors (PRR) of the innate immune cells are capable of immediately recognizing PAMPs as well as danger-associated molecular patterns (DAMPs) expressed by damaged cells. Pattern recognition receptors such as Toll-like receptors (TLRs) and C-type lectins (CTLs) expressed on the plasma membranes or NOD-like receptors and RigI-helicases in the cytoplasm, once activated by their ligands, lead to the activation of intracellular signal transduction pathways and induction of proinflammatory cytokines such as IL-1, IL-6, IL-12, IL-18, tumor necrosis factor (TNF), and interferons (IFN) which in turn regulate the adaptive immune response [1, 6, 11]. While the innate immune response has been traditionally defined as a nonspecific rapid response without memory, recent studies have shown that recognition of various PAMPs by different PRRs enables identification of pathogens [11], and especially NK cells can deliver specific memory responses [12]. A long-term enhanced state of innate immunity through epigenetic reprogramming has been recently identified as a significant property of innate host defense mechanisms [12]. Hereditary autoinflammatory disorders are associated with mutations of genes coding for proteins involved in the regulation of innate immunity [9, 10, 13]. These rare disorders are characterized by seemingly unprovoked episodes of inflammation and absence of autoreactive T cell or B cell responses [9, 10, 13]. There are also an increasing number of complex inflammatory disorders where autoinflammatory mechanisms are mainly involved in the pathogenesis, but adaptive immunity also plays a significant role in the chronicity of inflammation and target organ damage [1, 9, 14, 15].

The adaptive immune system cells, T and B lymphocytes, can specifically recognize pathogens and build memory for protection against reinfection. Specific recognition of pathogenic microorganisms by T cell receptors (TCR) and B cell receptors (BCR) is mediated by a variable-diversity-joining (V-D-J) gene recombination process [1, 6]. This process enables generation of a vast repertoire of TCR and BCR that can recognize an unlimited number of foreign antigens but also carries the risk of self-antigen recognition. Self-damage is normally prevented by central and peripheral tolerance mechanisms. Loss of tolerance to self-antigens and development of autoantibodies and autoreactive antigen-specific T cells lead to autoimmune disorders [6].

Environmental factors, most importantly, bacteria, viruses, other pathogens, as well as vaccines, are thought to play a central role in the induction and perpetuation of autoinflammatory and autoimmune disorders in genetically susceptible individuals [6, 7, 16, 17]. Several putative mechanisms have been postulated to explain triggering of autoimmune disorders by infectious agents [7, 16]. Antigen-specific mechanisms include molecular mimicry and cross-reactivity between foreign and self-antigens; activation of autoreactive T cells by superantigens produced by bacteria, mycoplasmae, or virus-infected cells; and expression of modified self-epitopes secondary to infection-mediated inflammation. Bystander activation and epitope spreading may also lead to a nonspecific immune response toward different self-antigens [7, 16]. It is difficult to incriminate a given infectious agent in an immune-mediated disease because the triggering infection may have taken place years before the clinical expression of the disease, latent infection or seroprevalence may be high in the healthy population, and laboratory identification of triggering infection may be limited. Furthermore, several different pathogens can trigger a single autoimmune disease, and a given pathogen can trigger various immune-mediated diseases. Complex interactions between immunogenetic factors and various infectious agents have not been completely understood yet.

Based on experimental models of autoimmune uveitis (EAU), the inciting event in human uveitis is most likely the activation of innate immunity outside the eye [2–4]. The activation of effector T cell subsets depends on the conditions under which exposure to a retinal or cross-reactive antigen occurs. In the classic EAU, immunization with interphotoreceptor retinoid-binding protein (IRBP) emulsified in complete Freund’s adjuvant (CFA), which contains heat-killed tuberculosis bacteria, derives differentiation of effector T cells toward Th17 phenotype, and a monocytic inflammatory response develops in the eye [2–4, 18]. In the more recent EAU model, injection of IRBP pulsed in dendritic cells matured in vitro with bacterial LPS derives a Th1 effector phenotype response, and the nature of inflammatory infiltrate in the eye is granulocytic, producing a fundus picture different from that seen in classic EAU [2, 3, 18]. Thus, quality and quantity of innate receptor stimulation by exogenous stimuli (infectious agents) seem to determine the immunological response profile as well as pathological and clinical features of intraocular inflammation. These findings in EAU may help explain the role of inciting stimuli on the heterogeneity of human uveitis.

Behçet disease (BD) is a multisystem inflammatory disorder characterized by oral and genital ulcerations, skin lesions, and uveitis, as well as involvement of joints, blood vessels, central nervous system, and gastrointestinal system [19]. Patients with BD have seemingly unprovoked recurrent inflammatory episodes in all organ systems involved [20]. Ocular involvement is characterized by a recurrent nongranulomatous panuveitis and occlusive retinal vasculitis and tends to be more severe and sight-threatening than most of the other forms of noninfectious uveitis [21, 22].

Pathogenetic mechanisms underlying BD include complex interactions between genetic factors, environmental factors, and immunological aberrations [20, 23–25]. Genome-wide association studies (GWAS) have confirmed that the known association with HLA-B51 is the strongest genetic factor for the development of BD. Recent GWAS have also identified novel susceptibility genes within the HLA class I region and variants in IL-10, IL23R-IL12RB2, STAT4, CCR1, and ERAP-1 [26–30]. BD-associated noncoding CCR1 allele is implicated in impaired microbial clearance [26, 31]. Epistasis was found between HLA-B51 and ERAP-1 variants which is an enzyme that trims peptides for proper loading onto the HLA class I molecule [26]. Additional associations with rare variants were discovered, including TLR4, MEFV, and NOD2 genes, which are associated with an increased responsiveness to bacterial products [30, 31]. These findings implicate defects in sensing and processing of pathogen and danger signals as well as in genes encoding pivotal proteins involved in Th1 and Th17 regulation [30]. A more recent genetic imputation study implicated the role of peptide-MHC-I binding and involvement of NK and cytotoxic T cell activation by MHC in the pathogenesis of BD [32].

Environmental factors, mainly infectious agents, have long been considered in the pathogenesis of BD. Infections are suspected in the initial triggering of the disease as well as in relapses of its manifestations [33]. However, there is no single microorganism that can be blamed as the specific etiologic agent. Oral microbial flora, especially Streptococcus species, colonizing in the oral cavity, may be the trigger of oral ulcers, the most common initial manifestation of the disease [23–25, 33, 34]. Streptococcus sanguis, S. salivarius, S. mitis, and S. mutans are associated with frequent oral infections [23]. Clinical observations of poor oral hygiene, dental caries, periodontitis in BD patients, and initiation or relapses of the disease following dental procedures or tonsillitis suggest the role of oral microbiota and Streptococcus [23, 24]. Behçet patients have high serum antibody titers and increased T cell reactivity and skin hypersensitivity to Streptococcus antigens. Furthermore, a favorable disease course is observed following improvement of oral hygiene and long-term control of dental and periodontal problems as well as following prophylactic penicillin treatment [23, 33]. Other bacteria that have been implicated as potential triggers include mycobacteria, Borrelia burgdorferi, Escherichia coli, Staphylococcus aureus, Mycoplasma fermentans, and Helicobacter pylori [25].

A triggering role of viruses has also been postulated, and especially the role of herpes simplex virus (HSV) has been the main focus of research [35]. An HSV-induced BD mouse model has been developed, based on the induction of several inflammatory lesions resembling manifestations of BD after inoculation of scratched earlobes with HSV 1 [35]. Other viruses that have been implied in the pathogenesis of BD include herpes virus 6 and 7, varicella-zoster virus (VZV), cytomegalovirus (CMV), parvovirus, Epstein-Barr virus (EBV), and hepatitis A, B, and C virus (HCV) [23, 25, 35]. Tripartite motif-containing (TRIM) proteins have key roles in antiviral immunity either by restriction of viral replication cycle or by regulating pathways mediated by pattern recognition of viral RNA/DNA and the inflammasome [36]. TRIM proteins induce production of type I interferons and proinflammatory cytokines such as IL-1β and thus may be involved in the pathogenesis of autoimmune and autoinflammatory responses [36]. TRIM proteins that have been specifically implicated in the pathogenesis of BD include TRIM39 and TRIM19 which functions in innate defense mechanisms against HSV [35].

It is thought that an aberrant immune response may be generated to different microorganisms recognized by pattern receptors in genetically susceptible individuals. Heat shock proteins are highly conserved molecules inducible by any form of cellular stress and act as intracellular scavenger and adjuvant [37]. Human HSP60, included in the DAMPs, has a high sequence homology with the mycobacterial HSP65 and also cross-reacts with streptococcal HSPs [23, 33]. Innate immune cells as well as γδT cells are stimulated by HSPs, through TLR2 and TLR4 expression. Differential TLR stimulation by microbial agents and their products and subsequent cytokine production by innate immune cells may lead to the skewed T cell responses observed in BD [34, 37, 38]. Alternatively, cross-reactivity of human HSPs with bacterial or viral HSP may derive the selection of autoreactive T cells resulting in perpetuation and chronicity of inflammation [37]. In summary, an impaired microbial clearance and exuberant innate and adaptive immune responses to microbial products may have a major contribution to the pathogenesis of BD.

Sarcoidosis is a multisystem chronic inflammatory disorder characterized by formation of noncaseating granulomas. Although the lungs and thoracic lymph nodes are most commonly affected, other lymph nodes, skin, salivary glands, liver, spleen, kidneys, heart, joints, nervous system, orbit, and eyes may also be involved [39]. Patients may also present with bilateral granulomatous intraocular inflammation in the absence of extraocular manifestations [40]. Characteristic features of ocular sarcoidosis include mutton-fat granulomatous keratic precipitates, iris and trabecular meshwork nodules, snowball vitreous opacities, chorioretinal lesions, nodular and/or segmental periphlebitis, retinal arterial macroaneurysms, and optic disc or choroidal nodules [40].

The etiology of sarcoidosis is not known. Genetic susceptibility, noninfectious environmental agents, and infectious triggers have been considered in the pathogenesis. In genetically susceptible individuals, a dysregulated immune response to one or more antigens may lead to a granulomatous inflammation characterized by infiltration of monocytes, macrophages, and activated T lymphocytes [41]. Genetic studies have shown class I HLA-B7 and HLA-B8 associations as well as associations with class II HLA-DRB1 and HLA-DQB1 that have been confirmed by recent GWAS. Immunologically relevant non-HLA genes have also been identified, including CARD15 (NOD2), butyrophilin-like protein 2 (BTNL2), and annexin A11 (ANXA11) [39, 41, 42]. CARD15 (NOD2) is an intracellular PRR, and polymorphisms of this gene are associated especially with early-onset sarcoidosis or Blau syndrome. BTNL2 is a member of the immunoglobulin superfamily and functions as a negative costimulatory molecule downregulating T cell activation. BTNL2 G16071A polymorphism found in sarcoidosis patients leads to loss of function of BTNL2 and thus could result in amplified T cell activation [41, 42]. ANXA11 is presumed to be a regulator of cell division and apoptosis; and interactions between ANXA11 and class II HLA genotypes have been identified in sarcoidosis [43].

Several noninfective environmental and occupational risk factors have been implicated, such as exposure to rural irritants, insecticides, inorganic particles, nanoparticles, metals, moldy environments, and fire [41, 44, 45]. However, no single cause of sarcoidosis was identified in ACCESS (a case-control etiologic study of sarcoidosis), although positive associations were found with agricultural employment, insecticides at work, moldy environments with possible exposures to microbial bioaerosols, and occupational exposure to insecticides [46]. Inappropriate processing of ubiquitous foreign agents may be the cause of chronic granulomatous inflammation in sarcoidosis patients.

Among infectious triggers, Mycobacterium tuberculosis has been suggested as the major causative agent [42, 44, 47]. Sarcoid specimens do not classically contain live M. tuberculosis organisms. Cell wall-deficient mycobacterial remnants have been shown in some specimens, and PCR studies have shown presence of mycobacterium DNA in sarcoidosis tissues [44, 47]. In a meta-analysis of studies reporting PCR identification of mycobacteria in sarcoid samples, the overall rate of positivity was 26 % and suggested a 9- to 19-fold increased odds compared to non-sarcoidosis controls [48]. The presence of Mycobacterium tuberculosis catalase–peroxidase (mKatG) and katG DNA in sarcoidosis tissues and almost half of sarcoidosis patients having serum antibodies to mKatG are further evidence to a mycobacterial etiology in at least a subset of sarcoidosis patients [44, 49]. mKatG is a virulence factor that allows prolonged survival of mycobacteria inside macrophages, and dysfunctional mKatG is associated with isoniazid resistance [49]. It has been hypothesized that mKatG may only be a component of mycobacterial antigens that form a nidus in sarcoid granulomas [49]. The potential of nontuberculous mycobacteria to cause sarcoidosis has been suggested as well [42, 47]. Propionibacterium acnes, Borrelia burgdorferi, herpes viruses, and EBV have also been implicated as potential causes of sarcoidosis, mostly based on an increased seroprevalence of these agents in the patient populations [44]. However, nonspecific polyclonal hypergammaglobulinemia is a feature of sarcoidosis and may account for increased antibody titers. Notably, Yasuhara et al. [50] have identified P. acnes and P. granulosum DNA by PCR analysis of vitreous specimens in six patients with sarcoid uveitis.

In summary, it is currently thought that multiple different antigens may be capable of inducing an aberrant immune response leading to manifestations of sarcoidosis in genetically susceptible individuals.

Vogt-Koyanagi-Harada (VKH) disease is a systemic autoimmune disorder that affects tissues containing melanin such as the eye, inner ear, meninges, and skin. The disease is characterized by chronic bilateral panuveitis associated with exudative retinal detachment along with a varying constellation of auditory, neurological, and cutaneous manifestations [51, 52].

While the exact etiology of VKH disease is unknown, it is thought to be a T cell-mediated immune process that is directed at the melanocytes [53–55]. Vogt-Koyanagi-Harada disease has a prodromal phase characterized by vague systemic symptoms suggestive of viral infection; therefore, infectious agents are thought to be the inciting factors for this autoimmune disease. Molecular mimicry and cross-reaction are the mechanisms used to explain the association of autoimmunity and viral infection [53]. The presence of EBV genome in cerebrospinal fluid and vitreous of patients with VKH has been shown [56]. A cross-reactive T cell response between tyrosinase peptides, which are postulated as target antigens on melanocytes and CMV antigen in patients with VKH disease, has also been described [57, 58]. It is assumed that there may be a molecular mimicry between some viruses and melanocytes; however, a clear association between a specific viral agent and the disease has not been established yet.

HLA-B27-associated anterior uveitis is a distinct clinical entity which has frequent associations with a group of systemic diseases called seronegative spondyloarthropathies (SSpAs). Seronegative spondyloarthropathies are a group of chronic inflammatory disorders characterized by an absence of serum rheumatoid factor and a strong association with the HLA-B27 antigen. Ankylosing spondylitis, reactive arthritis, psoriatic arthritis, arthritis and inflammatory bowel disease, and juvenile-onset spondyloarthropathy as a form of juvenile chronic arthritis are included in the spectrum of SSpAs. Uveitis is the most common extra-articular manifestation of seronegative arthritis [59].

HLA-B27-associated anterior uveitis is characterized by unilateral, alternating, recurrent, nongranulomatous acute anterior uveitis with significant protein and cellular extravasation into the aqueous humor that may be associated with fibrin and hypopyon formation [60–64].

In this group of uveitis patients, HLA-B27 positivity allows naming the entity; however, the precise molecular and pathogenic mechanisms linking HLA-B27 and uveitis are not completely understood. The expression of HLA antigens was found to be upregulated in the iris of patients with anterior uveitis, and this induction of HLA-antigen expression on iris cells may play a role in the pathogenesis of HLA-B27-associated anterior uveitis [65].

The underlying pathogenic mechanism is believed to be an interaction between genetic and environmental factors. Triggering role of bacterial infections in the pathogenesis of anterior uveitis and other HLA-B27-associated disease is suggested. In the well-characterized transgenic B27 model of SSpAs, the presence of normal microbial gut flora is required to induce disease. The finding that animals raised in germ-free conditions do not develop disease in this model also confirms the role of infections [66]. Endotoxin-induced uveitis in animal models is based on the induction of uveitis by bacterial products [67]. There is also evidence that links gastrointestinal tract infective and inflammatory abnormalities to extraintestinal manifestations of SSpAs such as uveitis and arthritis in humans [66].

Chang et al. [68] demonstrated the presence of toll-like receptor 4 and its associated lipopolysaccharide receptor complex in the human uvea. This study gives molecular insights into the potential mechanisms in which Gram-negative bacterial triggers may be involved in the development of anterior uveitis. Bacteria that have been implicated as potential triggers include Chlamydia trachomatis [69], Helicobacter pylori [70], and the Gram-negative enterobacteria including Klebsiella [71–74], Salmonella [75–77], Yersinia [78–82], and Campylobacter jejuni [60, 78, 83]. However, there are also some studies which have failed to show an association between these microorganisms and the etiology of anterior uveitis [84–87].

The fact that several infective etiologies appear to play a role in the pathogenesis of SSpAs has led to several hypotheses regarding etiopathogenesis. According to molecular mimicry hypothesis, there is an antigenic similarity between HLA-B27 and certain bacterial microorganisms, which may result in development of pathogen- or autoreactive T cells and consequently formation of an autoimmune chronic disease [88, 89]. Another postulated hypothesis suggests that HLA-B27 molecule may function as a receptor. Exogenous peptide derived from bacteria or endogenous protein produced as a result of an infection might be presented to cytotoxic T cells by the HLA-B27 molecule, activating the immune response [90].

In summary, HLA-B27-associated anterior uveitis is a common form of inflammatory eye disease, and recent advances in clinical and experimental research have shown the triggering role of bacteria in the etiopathogenesis of this disease. However, still many questions remain unanswered, and the cause of HLA-B27-associated anterior uveitis remains unclear.

Fuchs uveitis syndrome (FUS) is a low-grade, chronic, intraocular inflammatory disease of unknown origin. The disease has well-defined characteristics such as diffuse, scattered, and small- and medium-sized keratic precipitates with mild anterior chamber flare and minimal cells along with iris atrophy which may lead to acquired heterochromia in the absence of posterior synechiae and macular edema. Unlike other uveitis entities, FUS does not respond to corticosteroid therapy. Cataract formation and glaucoma are the main complications that may develop during the course of the disease [91–94].

The etiopathogenic mechanism of FUS remains elusive. Many theories regarding the etiology have been proposed, including genetic, sympathetic, infectious, neurogenic, and immunologic-inflammatory, but none of them was able to explain the whole pathogenesis [95, 96]. After recent improvements in diagnostic laboratory techniques for identification of infectious agents, the infectious theory has become of major interest to the researchers. A number of infectious causes have been proposed, including toxoplasma, rubella, CMV, and HSV [97, 98]. There are also some sporadic cases showing FUS following ocular Toxocara canis [99, 100], chikungunya [101, 102], and ophthalmomyiasis [103] infections.

Initially Fuchs [104] and Kimura et al. [105] described the association of peripheral retinochoroidal scars with FUS, which raised the possibility of ocular toxoplasmosis as an etiologic factor. Toledo de Abreu et al. [106] have reported the first study in the literature in which an association between ocular toxoplasmosis and FUS has been based on the clinical findings by showing presence of retinochoroidal scars in 56.5 % of FUS patients. In the vast majority of studies, an assumed association between FUS and ocular toxoplasmosis was implicated based on presence of retinochoroidal scars at variable frequencies [104–108]. Nevertheless, a few sporadic cases of FUS in congenital ocular toxoplasmosis [109] and at the time of an active toxoplasmic retinochoroiditis in the same eye [106, 110, 111] or in contralateral eye [112] have also been reported.

Ocular toxoplasmosis in all these different presentations may be responsible for triggering the onset of FUS via a complex pathway by inducing autoimmunity directed against retinal or choroidal antigens. However, at what level the connection exists is a matter for debate. Different theories have been postulated. The most recent immunological theory suggests that FUS may develop over a period of time after congenital or acquired ocular toxoplasmosis and it may be a secondary immune reaction with a past antigenic stimulation to a previous infection rather than reactivation of ocular toxoplasmosis [107]. On the other hand, in FUS cases with active ocular toxoplasmosis, immunologic antigens may be released into general circulation due to retinal destruction by proliferating organism, which may also result in sensitization, thereby causing inflammation in the same eye or in contralateral eye [107].

In more recent studies, viral etiologies including rubella and CMV have also been postulated in the pathogenesis of FUS. The presence of rubella virus genome and demonstration of intraocular production of antibodies against the rubella virus point out toward the possibility of rubella virus as a possible etiological agent [113, 114]. In 2004, Quentin and Reiber [113] were the first to find an evidence of intraocular synthesis of rubella antibodies in the aqueous humor of all of 52 patients with FUS and rubella genome in 18 % of the tested aqueous humor samples. Groot-Mijnes et al. [114] also confirmed the presence of rubella infection by showing a positive Goldmann-Witmer index for rubella virus in 93 % of FUS patients. Similarly a number of other groups also conducted independent studies confirming these findings [115–117]. Another indirect evidence supporting this hypothesis is that the incidence of FUS has been shown to decline significantly among the vaccinated population in a tertiary center after the initiation of measles-mumps-rubella vaccination program in the United States [118]. Still the relationship between the rubella virus and FUS is not clear. It is hypothesized that the intraocular immune response against the rubella virus as a result of delayed manifestations of a congenital or acquired rubella infection may be the inciting factor for the development of FUS [115].

Chee et al. [119, 120] were the first to postulate CMV as another possible etiological agent in the pathogenesis of FUS by showing presence of CMV DNA in aqueous humor of eyes with presumed FUS. It is possible that different infectious agents may be the triggering cause of FUS in different geographic regions.

In summary, none of these pathogens has been fully linked to FUS. Fuchs uveitis syndrome may be a secondary phenomenon or a final common pathway following an initiating event caused by various triggers.

Serpiginous choroiditis is a chronic, progressive, recurrent, and usually bilateral intraocular inflammatory disease of unknown origin. It is characterized by a geographic pattern of choroiditis, which typically extends from the peripapillary area and affects the overlying retinal pigment epithelium and the outer retina [121, 122].

Serpiginoid choroiditis, also described as serpiginous-like choroiditis, multifocal serpiginous choroiditis, multifocal serpiginoid choroiditis, or ampiginous choroiditis, may present as multifocal progressive or diffuse choroiditis resembling serpiginous choroiditis [123–128]. However, unlike serpiginous choroiditis, ocular involvement in serpiginoid choroiditis is usually unilateral, with multifocal irregular serpiginoid lesions involving the posterior pole, mid-periphery, and periphery sparing the juxtapapillary area. There is typically a prominent inflammatory cellular reaction in the vitreous and/or anterior chamber in this form [121].

Serpiginous choroiditis is primarily considered as an immune-mediated disease. An increased frequency of HLA-B7 and retinal S antigen association has been reported [129, 130]. Infectious triggers have also been postulated in the etiopathogenesis. Despite an association with syphilis has been shown [131, 132], the most often considered triggering bacterial infection is Mycobacterium tuberculosis [133–135]. However, antituberculosis chemotherapy has been shown to fail to halt the progression of the disease [136]. Furthermore, in contrast to serpiginoid choroiditis, patients with serpiginous choroiditis are usually from areas where tuberculosis is not endemic and patients mostly reveal negative results for tuberculin skin test, interferon gamma release assay, and chest x-ray [121].

In serpiginous choroiditis patients, a possible association with herpes viruses has also been postulated [137–139]. In PCR studies, VZV, HSV, CMV, and EBV genome has been shown to be positive in the aqueous humor of patients with serpiginous choroiditis; however, it is not clear whether antiviral treatment can halt choroiditis progression or recurrence [137, 138]. Interestingly, Candida species were also postulated as another possible etiological agent in a case series, which has not been confirmed by any other studies [140]. Still, evidence suggests that serpiginous choroiditis is primarily an idiopathic or autoimmune disease which can be treated with a combined regimen of oral corticosteroids along with immunomodulatory agents and not with anti-infectious agents [121].

Mycobacterium tuberculosis DNA was shown to be positive in the aqueous and vitreous humor of patients with serpiginoid choroiditis, and unlike serpiginous choroiditis, the disease shows good response to systemic antituberculosis chemotherapy [123, 124, 141]. Interestingly, in a recent PCR study, EBV DNA was also shown to be positive in the aqueous humor of patients with serpiginoid choroiditis [138].

Although various infections may be the inciting factors, serpiginous choroiditis and serpiginoid choroiditis are two different entities with different clinical morphology and management. The precise etiopathogenesis of each of these disorders remains unknown.

Birdshot chorioretinopathy is an uncommon form of idiopathic bilateral posterior uveitis characterized by multiple, distinctive, hypopigmented choroidal lesions which are typically seen in middle-aged women of Caucasian origin [142, 143].

The disease has a strong genetic association with the HLA-A29 antigen, which suggests that genes for major histocompatibility antigens may play a role in the pathogenesis of the disease. Still, the immune mechanism involved in the pathogenesis remains unclear [144]. It is presumed that an infectious agent may initiate an immune response either by itself or through molecular mimicry in a genetically predisposed person by facilitating the presentation of autoantigen to T cells by the HLA-A29 molecule [142, 145]. Borrelia burgdorferi and Coxiella burnetii are the two organisms postulated as potential etiologic agents; however, there is still no study showing the direct role of infectious agents in the pathogenesis [146–148].

Inflammatory chorioretinopathies, referred to as “white dot syndromes,” are a group of disorders of unknown etiology characterized by multiple discrete whitish-yellow inflammatory lesions located at the various levels of the retina, outer retina, retinal pigment epithelium, choriocapillaris, and choroid [149, 150]. Acute posterior multifocal placoid pigment epitheliopathy (APMPPE), multiple evanescent white dot syndrome (MEWDS), multifocal choroiditis with panuveitis (MFC), and punctate inner choroiditis (PIC) are the disease entities included in the spectrum of white dot syndromes [151]. Common presenting symptoms include photopsias, blurred vision, floaters, nyctalopia, and visual field loss (blind spot enlargement), and some of these syndromes are also associated with an antecedent prodromal illness characterized by flu-like symptoms. Most of these entities are more commonly seen in myopic young women [149].

While the etiology of the white dot syndromes is not completely understood, various mechanisms have been postulated including infectious and noninfectious causes. Jampol et al. [152] suggested that a variety of relatively common susceptibility genes which probably also correspond to the ones that have been identified for systemic autoimmune diseases are present in patients with white dot syndromes. These loci are thought to be not disease specific and environmental triggers such as infections, immunizations, stress, and other factors (age, other genetic factors, sex) interact to predispose these individuals to particular ocular disorders. Since these patients have underlying shared susceptibility genes, they may also develop more than one of these disease entities and are also predisposed to recurrences [152]. An infectious cause, viral in particular, as an environmental trigger has been suggested based upon suspected or documented infections for some of these disorders.