MALT lymphoma is a form of lymphoma involving the Mucosa-Associated Lymphoid Tissue (MALT) that has distinct features from all other forms of primary non-Hodgkin extranodal lymphoma (Figure 5). Ocular adnexal lymphoma is primarily found in older adults with a slight female preponderance. It occurs in the orbit, conjunctiva, and lacrimal gland, in decreasing order of frequency of involvement.138 From a histological point of view, this condition is characterized by a large prevalence of marginal zone B-cell histologic types and a varying degree of infiltrating reactive T-cells.139 The clinical manifestations depend on the identity of the compromised structures. For example, 25% of MALT lymphoma displays conjunctival involvement. Intra-orbital masses are present in 75% of cases, while bilateral involvement occurs in 10%–15% of cases.138 Intraorbital lymphoma is variably associated with exophthalmos, palpable mass or nodule, eyelid ptosis, diplopia, epiphora, and impaired ocular motility.140 Its clinical presentation usually consists of a single, slowly growing, painless mass that displaces the normal structures; however, its presentation can also be acute, with inflammatory-like signs and symptoms. Ocular infiltration is exceptional.141 Gastric MALT is known to be acquired in response to local infection by Hp, which is present in greater than 90% of these lymphomas.142 To colonize in the stomach, Hp must overcome the acidic environment of the stomach and then the gastric mucous layer. The hydrolysis of urea with the generation of ammonia may enable survival of this acid-sensitive organism in the gastric mucosa. Furthermore, ammonia generated by urea hydrolysis may also produce severe cytotoxic effects within the gastric epithelium.143 Due to the spiral shape and multiple polar flagella, which are used for motility,144 Hp stick out through the mucous layer and reach the gastric epithelium, where they sticks to its cells using the adhesins.145 Among infected individuals, approximately 10% develop peptic ulcer disease; 1% to 3% develop gastric adenocarcinoma; and <0.1% develop MALT lymphoma.146 The contact between Hp and the gastric epithelium generates an immune and inflammatory response.147 This activates the transcription factor NF-kB, inducing proinflammatory chemokines and recruiting neutrophils, monocytes, macrophages, and dendritic cells.148–151 Furthermore, this response regulates processes connected with B-cell development, growth, and survival by producing cytokines and growth factors and can also be responsible for activating cell apoptosis.152 Then, an adaptive immune response to the Hp infection emerges from the macrophages and dendritic cells located in the lamina propria of the gastric mucosa.150,153 Neutrophils, monocytes, and macrophages may phagocytose Hp, but they seem to be able to achieve this without intracellular killing,154 as Hp can survive within monocytes for up to 48 hours.155 The failure of the immune response to eliminate Hp results in chronic inflammation of the gastric mucosa. The sequential progression from chronic inflammation to mucosal atrophy, metaplasia, and dysplasia leads to carcinogenesis.156 In a small subset of individuals, chronic inflammation due to a persistent Hp infection can give rise to organized lymphoid tissue in the gastric mucosa, ultimately progressing to low-grade gastric B-cell lymphoma of the MALT type.157 Immunity to Hp and gastric immune-mediated damage is dependent on T cells.158 The prolonged interaction between the bacteria and the host immune mechanisms makes Hp a plausible infectious agent for triggering autoimmunity via molecular mimicry. The tumor cells of low-grade gastric MALT lymphoma (MALToma) are B cells that are still responsive to differentiation signals, such as cytokines produced by antigen-stimulated T cells, and that are dependent on stimulation by Hp-specific T cells for growth.157,158 The activity of these specific T cells, which are defective in both perforin- and Fas ligand-mediated cytotoxicity, consequently promotes both B-cell overgrowth and exhaustive B-cell proliferation.159 In the gastric mucosal cells, there are elevated levels of cytokines, including proliferation-inducing ligand (APRIL), which belongs to the tumor necrosis factor family. APRIL is produced by macrophages present in the gastric MALT infiltrate, close to the neoplastic cells,160 and may also induce B-cell transformation and their progression to diffuse large B-cell lymphoma. APRIL production by macrophages can be enhanced and maintained by activated T lymphocytes.161 The survival and transformation of B cells in malignant lymphoma require additional signals. They come either from T cells or directly from the antigenic autostimulation of lymphoma cells. Therefore, one or more neoplastic clones, derived from a gastric MALToma, are able to express molecules that powerfully stimulate B-cell activation and proliferation,162 colonize and replace the original follicles, eventually destroying the gastric glands to form lympho-epithelial lesions,163 and finally precipitate the onset of low-grade gastric MALT lymphoma. Although MALT lymphoma usually grows slowly and has a low propensity to spread, a small percentage of cases undergo high-grade transformations.
Many MALT lymphomas at non-ocular sites are associated with an infectious etiology, supporting the model of antigen-driven lymphoma genesis.164 According to this model, an infection first triggers the chronic antigen stimulation of B cells and the production of antibodies. The proliferation of B cell clones becomes antigen-independent, and with uncontrolled proliferation, malignant transformations can occur.164 However, not all those with an Hp infection also have a MALT lymphoma. This indicates that the role played by genetic factors, is of great importance, as gastric MALT lymphoma presents with a series of recurrent genomic lesions, including chromosomal translocations and unbalanced aberrations. The accumulation of genetic abnormalities is associated with a loss of dependency from antigenic stimulation (with subsequent antibiotic resistance) and a possible histologic transformation.165 Moreover, 10%–20% of patients do not respond to Hp eradication treatments. This group often has a chromosome translocation, which suggests that there is another pathogenetic mechanism of MALT lymphoma that is thus far unknown.161
A higher incidence of MALT lymphoma has been reported in patients with chronic Hp infections, as well as in those with Sjögren syndrome.158 Similarly, patients with Sjögren syndrome have a much higher incidence of developing lymphoma, most of which are MALT type.166 Further studies are needed before Hp can be implicated as a significant contributor to the etiology of conjunctival MALT lymphoma.
Uveitis is a term used to describe different forms of intraocular inflammation involving the uveal tract of the eye; it is classified by anatomical location and time course of the disease.167 Acute anterior uveitis, also known as iridocyclitis or iritis, is an inflammatory disorder of the iris and/or pars plicata (anterior ciliary body) and anterior chamber that lasts no longer than 3 months. Intermediate uveitis, or pars planitis, consists of vitritis, defined as an inflammation of the cells in the vitreous, sometimes with snow banking, or the deposition of inflammatory material on the pars plana. Posterior uveitis indicates inflammation in the retina and/or choroid. Uveitis is a rare disease that is particularly prevalent in younger people.168 The etiological diagnosis of anterior uveitis can be established in approximately 60% of cases, while 75% of patients with intermediate uveitis remained without specific diagnosis. A specific diagnosis could be established in 78% of patients with posterior uveitis. Uveitis infections accounted for approximately 20% of the above cases.169 Otasevic et al170 have demonstrated that a high percentage of antibodies to Hp in the serum of a group of patients with acute anterior uveitis, some of whom were affected by spondyloarthropathies. Unfortunately, the sample examined was too small to allow for any concrete conclusions. Kim et al171 have detected on a sample of 165 subjects that Hp infection is associated with high IOP in anterior uveitis, but without finding a real causal connection between Hp infection and ocular hypertension. Thus, uveitis involved in a multitude of diseases; many chronic inflammatory diseases are associated with an elevated risk of uveitis, eg, rheumatoid arthritis, ankylosing spondylitis,172 Behcet disease,173 and Crohn disease.174 These diseases can induce other types of uveitis due to inflammation, even if they are not diagnosed as uveitis at the beginning. The breakdown of the blood-aqueous barrier in uveitis involves cellular infiltration, an increase in protein permeability, and the up-regulation of cytokines, such as TNF-α and IL-6, and chemokines, such as MCP-1, and MIP-1. In the aqueous humor and uveal regions,175 the exposure of the cells near the blood-aqueous barrier to inflammatory cytokines and chemokines could eventually cause cytotoxicity, leading to apoptosis or proliferation. Inflammation is associated with increased oxidative stress by elevated ROS, which could alter cellular and molecular targets and pathways crucial to normal tissue homeostasis.176,177 The generation of ROS in turn activates redox-sensitive transcription factors such as NF-κB, which controls the expression of a large number of genes involved in apoptosis, cell growth, survival, differentiation and immune response. Alterations in NF-κB activity are associated with a large number of diseases, including autoimmune, cancer and inflammatory diseases.178 NF-κB plays an important role in the regulation of immune and inflammatory responses. Pathogens, oxidants, cytokines, chemokines, and growth factors associated with oxidative stress trigger specific receptors and cause oxidative stress signaling cascades that lead to the activation of NF-κB. NF-κB activation is responsible for the expression of a wide variety of genes that encode cytokines (TNF, IL-1, IL-6), chemokines (MIP-1, MCP-1), adhesion molecules (ICAM, VCAM, E-Selectin), iNOS and Cox-2.175 ROS are important modulators of signaling pathways and can regulate both the apoptotic signaling and NF-kappaB transcription triggered by TNF. ROS can also cause redox modifications that inhibit NF-kappaB activation, leading to cell death triggered by TNF.179 The increased ROS levels during inflammation could be increased oxygen consumption in the uveitis or decreased antioxidative defense in the concerned tissue. The increased levels of ROS in the ocular cells cause a redox imbalance, leading to activation of redox signaling intermediates, which in turn activate transcription factors, including NF-κB, with the result of transcription of inflammatory marker genes.180,181 The reduced circulating levels of vitamin C in Hp infected subjects may contribute to the etiology of some diseases associated with antioxidant deficiency.182 The excessive ROS generation also weakens the tissue own antioxidant defense system, further aggravating the inflammation and ROS production and generating tissue damage in uveitis. This damage increases the level of metallo-proteases, which chew up intra-cellular and extracellular proteins, resulting in tissue injury.176 During Hp infection, activated macrophages produce the following pro-inflammatory cytokines: IL-1, IL-2, IL-6, IL-8, and TNF-α.183 Most of these cytokines are expressed in the aqueous humors of patients with idiopathic acute anterior uveitis.184 Therefore, the chance of an autoimmune reaction due to molecular mimicry may be possible.185,186
In conclusion, it is extremely difficult to compare the results of the studies that are currently available in the literature, as to do so would require a population-based study involving thousands of patients in order to effectively determine the prevalence of eye diseases in patients infected with Hp. Nevertheless, inadequate antioxidant protection or excess production of ROS creates conditions of oxidative stress, which is thought to play an important role in the aging of the eye and in many inflammatory eye diseases.5 In any case, it is difficult to understand how Hp infection can be linked to such varied pathologies. It is possible that this “link” might be the oxidative damage that recurs in circulatory disorders,187 inflammation188,189; and glaucoma.55,85 As we can also see in central serous chorioretinopathy and ocular adnexal MALT lymphoma, the effects of oxidative stress can be substantial. Inflammation in Hp infections and in eye diseases progresses through a series of common pathogenic aspects shared by the two entities, despite their differing clinical features. Indeed, adequate antioxidant defenses responsible for scavenging free radicals are essential for redox homeostasis and inhibition of inflammation. These are variables, eg, corneal epithelial cells have strong antioxidant defenses, conversely, other ocular tissues, such as the trabecular meshwork, are poorly equipped with antioxidant defenses and consequently less able to counteract injurious effects of ROS5 Therefore, therapy with antioxidants should prove beneficial for the clinical management of patients with Hp infection.190
Vitamin C appears to have a particularly important role, in fact within the cell, vitamin C helps to protect membrane lipids from peroxidation by recycling vitamin E.191 This could be relevant in all eye diseases that we talked about, especially in glaucoma where the Vitamin C has a direct effect on the trabecular meshwork where might improve their ability to degrade proteins within the lysosomal compartment and recover tissue function.192 Therefore Ascorbic acid supplementation may improve the effectiveness of Hp-eradication therapy.193 Besides, diets rich in naturally occurring ascorbic acid are associated with protection of the gastric corpus from atrophy and a reduction in the incidence of gastric cancer possibly through the ability of ascorbic acid to reduce oxidative damage to the gastric mucosa by scavenging carcinogenic N-nitroso compounds and free radicals and attenuating the Hp-induced inflammatory cascade.193 Further studies are required to prove that Ascorbate or other antioxidant supplementations have a significant impact on progress of the association between eye diseases and HP infection.
On the whole, the data reported in this review provide evidence that oxidative stress and inflammation represent common pathogenic mechanisms that play a major role in both Hp infection and several eye diseases.
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