Chronic Ocular Inflammatory Diseases Research Articles

Deceptology in cancer and vaccine sciences: Seeds of immune destruction-mini electric shocks in mitochondria: Neuroplasticity-electrobiology of response profiles and increased induced diseases in four generations - A hypothesis.

From Rockefeller's support of patent medicine to Gates' patent vaccines, medical establishment invested a great deal in intellectual ignorance. Through the control over medical education and research it has created a public illusion to prop up corporate profit and encouraged the lust for money and power. An overview of data on cancer and vaccine sciences, the status of Americans' health, a survey of repeated failed projects, economic toxicity, and heavy drug consumption or addiction among young and old provide compelling evidence that in the twentieth century nearly all classic disease categories (congenital, inheritance, neonatal, or induced) shifted to increase induced diseases. Examples of this deceptology in ignoring or minimizing, and mocking fundamental discoveries and theories in cancer and vaccine sciences are attacks on research showing that (a), effective immunity is responsible for defending and killing pathogens and defective cancerous cells, correcting and repairing genetic mutations; (b) viruses cause cancer; and (c), abnormal gene mutations are often the consequences of (and secondary to) disturbances in effective immunity. The outcomes of cancer reductionist approaches to therapies reveal failure rates of 90% (+/‐5) for solid tumors; loss of over 50 million lives and waste of $30‐50 trillions on too many worthless, out‐of‐focus, and irresponsible projects. Current emphasis on vaccination of public with pathogen‐specific vaccines and ingredients seems new terms for drugging young and old. Cumulative exposures to low level carcinogens and environmental hazards or high energy electronic devices (EMF; 5G) are additional triggers to vaccine toxicities (antigen‐mitochondrial overload) or “seeds of immune destruction” that create mini electrical shocks (molecular sinks holes) in highly synchronized and regulated immune network that retard time‐energy‐dependent biorhythms in organs resulting in causes, exacerbations or consequences of mild, moderate or severe immune disorders. Four generations of drug‐dependent Americans strongly suggest that medical establishment has practiced decades of intellectual deception through its claims on “war on cancer”; that cancer is 100, 200, or 1000 diseases; identification of “individual” genetic mutations to cure diseases; “vaccines are safe”. Such immoral and unethical practices, along with intellectual harassment and bullying, censoring or silencing of independent and competent professionals (“Intellectual Me Too”) present grave concerns, far greater compared with the sexual harassment of ‘Me Too’ movement that was recently spearheaded by NIH. The principal driving forces behind conducting deceptive and illogical medical/cancer and vaccine projects seem to be; (a) huge return of investment and corporate profit for selling drugs and vaccines; (b) maintenance of abusive power over public health; (c) global control of population growth via increased induction of diseases, infertility, decline in life‐span, and death.An overview of accidental discoveries that we established and extended since 1980s, on models of acute and chronic ocular inflammatory diseases, provides series of the first evidence for a direct link between inflammation and multistep immune dysfunction in tumorigenesis and angiogenesis. Results are relevant to demonstrate that current emphasis on vaccinating the unborn, newborn, or infant would induce immediate or long‐term immune disorders (eg, low birth weight, preterm birth, fatigue, autism, epilepsy/seizures, BBB leakage, autoimmune, neurodegenerative or digestive diseases, obesity, diabetes, cardiovascular problems, or cancers). Vaccination of the unborn is likely to disturb trophoblast‐embryo‐fetus‐placenta biology and orderly growth of embryo‐fetus, alter epithelial‐mesenchymal transition or constituent‐inducible receptors, damage mitochondria, and diverse function of histamine‐histidine pathways. Significant increased in childhood illnesses are likely due to toxicities of vaccine and incipient (eg, metals [Al, Hg], detergents, fetal tissue, DNA/RNA) that retard bioenergetics of mitochondria, alter polarization‐depolarization balance of tumoricidal (Yin) and tumorigenic (Yang) properties of immunity.Captivated by complex electobiology of immunity, this multidisciplinary perspective is an attempt to initiate identifying bases for increased induction of immune disorders in three to four generations in America. We hypothesize that (a) gene‐environment‐immune biorhythms parallel neuronal function (brain neuroplasticity) with super‐packages of inducible (adaptive or horizontal) electronic signals and (b) autonomic sympathetic and parasympathetic circuitry that shape immunity (Yin‐Yang) cannot be explained by limited genomics (innate, perpendicular) that conventionally explain certain inherited diseases (eg, sickle cell anemia, progeria). Future studies should focus on deep learning of complex electrobiology of immunity that requires differential bioenergetics from mitochondria and cytoplasm. Approaches to limit or control excessive activation of gene‐environment‐immunity are keys to assess accurate disease risk formulations, prevent inducible diseases, and develop universal safe vaccines that promote health, the most basic human right.

Abstract A06: ‘Accidental discoveries on systematic studies: Role of inflammation in multistep tumorigenesis and angiogenesis in models of allergies

Abstract Among major scientific factors involved in extremely slow progress in cancer research and failed therapies are the lack of understanding of host tissue composition and interactions between resident immune cells and signaling for recruited cells in carcinogenesis. In 1980s experimental models of acute and chronic ocular inflammatory diseases resulted in tumorigenesis and angiogenesis. Analyses of data became accidental discoveries for systematic identification of time-course kinetics of interactions and synergies between host immune cells (e.g., mast, goblet and B cells) and recruiting cells (e.g., eosinophils and TAMs) during acute, intermediate and chronic phases of immune dynamics caused induction of tumor-like lesions in conjunctival-associated lymphoid tissues. The data are the first multiple findings on early events, followed by sequential alterations of immunity toward tissue growth and angiogenesis. In 2008, acute inflammation or effective immunity was defined as the balance between two biologically opposing arms, termed Yin (tumoricidal) and Yang (tumorigenic) properties of immune and non-immune (e.g., vasculature, neurodegenerative and metabolic) responses. Chronic inflammation was hypothesized as loss of balance in Yin and Yang and a common link for genesis of all age-associated chronic diseases or cancer. Future efforts to promote immunity should include systematic understanding of host-pathogen interactions in susceptible tissues. Outcomes are expected to hold real promise in understanding how cancer cells become threat to body and how translate cancer biology into cost-effective drug designs and clinical trials. Note: This abstract was not presented at the conference. Citation Format: Mahin Khatami, Ret. ‘Accidental discoveries on systematic studies: Role of inflammation in multistep tumorigenesis and angiogenesis in models of allergies. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A06.

Abstract B25: Inflammation and cancer: standardizing biomarkers criteria (data elements) as foundation of a database. M-CSF used as prototype to test data elements

Abstract Lack of better understanding, whether inflammation is protective in preventing cancer or it is a cause for promoting cancer, reflected by continuous controversies and debates has significantly slowed down progress in preventing or treating cancer and many age-associated chronic diseases. Consequently, too many expensive and out of focus clinical trials that use potent pro-inflammatory mediators or inhibitors of growth factors (wound healing or tumorigenic) have caused life threatening side-effects such as cachexia, thrombosis, or drug-resistance and cancer-relapse resulting multiple organ failure (MOF) in cancer patients. Such approaches in ‘targeted’ or ‘personalized’ medicine for site-specific cancers that often result in MOF are similar to clinical features of potent pathogens-induced severe inflammatory diseases and MOF in sepsis or meningitis. In 1980's the results of our ‘accidental’ discoveries on experimental models of acute and chronic ocular inflammatory diseases are suggestive of the first evidence for a direct link between inflammation and tumorigenesis and angiogenesis. Analyses of data led to a first publication on inflammation-induced time course kinetics of developmental phases of immune dysfunction that resulted in neovascularzation, tumor growth and angiogenesis in conjunctival-associated lymphoid tissues (1984, 85, 88, 89, 90 a, b, 2005 a, b). Recently, acute inflammation was defined as highly regulated immune responses possessing 2 biologically opposing arms, termed ‘Yin’ (apoptosis or tumoricidal) and ‘Yang’ (wound healing or tumorigenic), capable of precise communications between immune and non-immune systems (e.g., neuroendocrine, vasculature) to protect the body against external and internal foreign elements including killing of cancer cells (cancer or immune surveillance). Unresolved inflammation was proposed as the loss of balance between ‘Yin’ and ‘Yang’ that could lead to expression of exaggerated and mismatched mediators creating immunological chaos or ‘immune tsunami’, and eroding architectural integrity and function of target tissues as the basis for induction and progression of chronic diseases or cancer. This presentation focuses on extension and integration of our ground breaking multidisciplinary data with emphasis on standardizing cancer biomarkers criteria through identifying data elements for nearly all cancer markers as a foundation of a cancer biomarkers database (2005 c). An inflammatory mediator (M-CSF) is used as prototype to tailor data elements (e.g., comparison of its superior sensitivity and specificity with conventional markers such as CA-125) as potential marker for technology development and diagnostic tools. A framework for design of clinical studies will be presented based on hypotheses that: a) Inflammatory mediators are ideal targets for diagnosis and treatment of cancer; b) Inflammation is a common denominator in the genesis of age-associated chronic diseases such as diabetes and cardiovascular complications or cancer; and c) maintenance of balance between ‘Yin’ and ‘Yang’ of acute inflammation is a key for preventing, avoiding or delaying the onset of age-associated chronic diseases or cancer (1999, 2005, 2007, 2008, 2009, 2011, 2012). Citation Format: Mahin Khatami. Inflammation and cancer: Standardizing biomarkers criteria (data elements) as foundation of a database. M-CSF used as prototype to test data elements. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B25.

New biologic-response modifiers in ocular inflammatory disease: beyond anti-TNF treatment

Current treatment guidelines for chronic ocular inflammatory disease recommend the use of steroid-sparing agents. The development of conventional immunomodulatory agents has largely changed the visual outcome in these patients. However, disease refractory to these treatment modalities has led to the use of new biologic-response modifiers, agents that target specific components of the pathogenetic process. The purpose of this review is to summarize the mechanism of action, experimental evidence, side effects and current experience with the use of rituximab, daclizumab, abatacept, anakinra and IFN-α in ocular inflammatory disease.

Combination of KIR and HLA gene variants augments the risk of developing birdshot chorioretinopathy in HLA-A*29-positive individuals

Birdshot chorioretinopathy (BCR), a chronic ocular inflammatory disease with characteristic choroidal lymphocytic infiltrates, has been strongly associated with human leukocyte antigen (HLA)-A29. Although HLA-A29 occurs frequently in all populations, BCR affects only a small percentage of HLA-A29-positive Caucasians, indicating additional susceptibility factors for BCR. Discovery of HLA class I-specific killer cell immunoglobulin-like receptors (KIR) led to a series of epidemiological studies implicating KIR-HLA gene combinations in disease. Here, we characterized KIR-HLA pairs in BCR patients and controls carrying HLA-A*29 as well as controls lacking HLA-A*29. KIR-HLA pairs implicated for weak inhibition (KIR2DL2/3+HLA-C1 and KIR3DL1+HLA-Bw4(T80)) in combination with activating KIR genes associated with autoimmunity (KIR2DS2, 2DS3 and 2DS4) augment the risk of developing BCR in HLA-A*29-positive individuals. The reciprocal association of strong inhibitory pairs (KIR3DL1+HLA-Bw4(I80) and KIR2DL1+HLA-C2) in combination with those implicated in protection from infection (KIR3DS1+HLA-Bw4(I80) and KIR2DS1+HLA-C2) was observed in HLA-A*29-negative controls. These results suggest that a profound effect of KIR2DS2/S3/S4 in the absence of strong inhibition may enhance the activation of natural killer cells and T-cell subsets against intraocular self-antigens, thereby contributing to pathogenesis of BCR.

Combination of KIR‐HLA genotypes implicated in weak inhibition and autoimmunity augments risk for Birdshot Chorioretinopathy in HLA‐A29 positive individuals

HLA‐A29 is strongly associated with birdshot chorioretinopathy (BCR), a chronic ocular inflammatory disease with characteristic choroidal lymphocytic infiltrates. Although HLA‐A29 occurs frequently in all populations, BCR affects only a small percentage of HLA‐A29 positive Caucasians, indicating additional susceptibility factors for BCR. Discovery of HLA class I‐specific killer cell immunoglobulin‐like receptors (KIR) led to a series of epidemiological studies implicating KIR‐HLA gene combinations in disease. Here, we characterized KIR‐HLA pairs in BCR patients and controls carrying HLA‐A29 as well as controls lacking HLA‐A29. We found that combination of KIR‐HLA genotypes implicated for weak inhibition (KIR2DL2/3+HLA‐C1 and KIR3DL1+HLA‐Bw4T80) and autoimmunity (KIR2DS2/S3/S4) augments the risk of developing BCR in HLA‐A29 positive individuals. The reciprocal association of strong inhibitory pairs (KIR3DL1+HLA‐Bw4I80 and KIR2DL1+HLA‐C2) in combination with those implicated in protection from infection (KIR3DS1+HLA‐Bw4I80 and KIR2DS1+HLA‐C2) was observed in HLA‐A29‐negative controls.

Interaction of Staphylococcus aureus peptidoglycan with toll-like receptor 2, but not platelet activating factor receptor, promotes TNFα release from human conjunctival epithelial cells

Rationale Staphylococcus aureus (SA) bacteria are found in large colony counts on the skin of 90% of patients with atopic dermatitis and could play a role in the pathophysiology of atopic keratoconjunctivitis (AKC). SA peptidoglycan (SA-PGN) can be recognized by Toll-like receptor 2 (TLR2) and Platelet Activating Factor Receptor (PAFR) expressed on epithelial cells resulting in release of pro-inflammatory cytokines such as TNFα. The purpose of this study was to examine the roles of TLR2 and PAFR in SA-PGN mediated release of TNFα from human conjunctival epithelial cells (HCE). Methods Primary HCE cultures were obtained by enzymatic digestion of cadaveric conjunctival tissues. TLR2 protein and mRNA expression by conjunctival epithelial cells (± IFNγ) were confirmed by flow cytometry and Northern blot analysis respectively. HCE were pre-incubated with/without TLR2 blocking antibody (A-TLR2) and/or PAFR antagonist (WEB2086) followed by stimulation with/without S. aureus PGN for 24 hrs. Supernates were harvested for TNFα ELISA. Results HCE expressed TLR2 protein and mRNA, following stimulation with IFNγ. SA-PGN stimulated TNFα release from HCE (1504.45 ± 340.15 vs. 700.64 ± 126.36 pg/10 6 cells for SA-PGN vs. unstimulated HCE respectively, p<0.05), which was inhibited in a dose dependent manner by A-TLR2. Inhibition was 47.9 ± 8.9% of SA-PGN stimulated TNFα release (20 μg/ml dose A-TLR2, p<0.05). PAFR antagonist had no effect on SA-PGN stimulated TNFα release alone or in combination with TLR2 blocking antibody. Conclusions SA-PGN mediated TNFα release from HCE via TLR2 may contribute to the pathogenesis of AKC and thus represent a target for treatment of this chronic ocular inflammatory disease.

Mycophenolate mofetil as an immunomodulatory agent in the treatment of chronic ocular inflammatory disorders

Purpose To evaluate the outcomes of patients with chronic ocular inflammatory disease treated with mycophenolate mofetil as an immunosuppressive and steroid-sparing agent. Design Retrospective noncomparative interventional case series. Participants All patients with ocular inflammatory disease treated with mycophenolate mofetil at a single institution between 1998 and 2001. Methods Charts of patients seen on the Ocular Immunology and Uveitis Service at the Massachusetts Eye and Ear Infirmary were reviewed. Patients with chronic ocular inflammatory disease were included in the study. Main outcome measures Control of inflammation, steroid-sparing effect, visual acuity, and adverse reactions were measured. Results A total of 54 patients were evaluated. Control of ocular inflammation with mycophenolate mofetil as monotherapy was achieved in 35 patients (65%) and in 67 eyes (62%), and a steroid-sparing effect was achieved in 29 (54%) patients. Visual acuity was maintained or improved in 51 patients (94%) and in 97 eyes (90%). Side effects requiring discontinuation of medication occurred in 10 patients (18%). There was neither long-term morbidity nor mortality due to mycophenolate mofetil. Conclusions Mycophenolate mofetil is effective in the treatment of patients with steroid-dependent or -resistant chronic ocular inflammatory disorders that fail to respond to conventional steroid treatment. It is a safe and effective steroid-sparing immunomodulatory agent and can be considered an important addition to our armamentarium in the care of patients with ocular inflammatory disease.

The Human Leukocyte Antigen Complex and Chronic Ocular Inflammatory Disorders

PURPOSE: To review the role of gene products from the human leukocyte antigen (HLA) complex in the normal functioning of the immune system, ocular inflammation, and models of autoimmunity. METHOD: A review of recently published reports. RESULTS: Many chronic ocular inflammatory diseases are associated with specific alleles of the HLA complex. Understanding how HLA gene products function normally provides clues to the mechanism of disease associations. In the thymus, these molecules control the shape of the developing T-cell repertoire, leading to self-tolerance. In the periphery, HLA molecules bind and present peptide fragments to T cells, leading to a variety of effector functions. Although effector functions are for the most part beneficial, models are reviewed in which peptide-HLA interactions lead to T-cell responses with pathologic consequences. Herpes stromal keratitis is an informative animal model highlighting the role of self-tolerance, infection, and molecular mimicry in the development of autoimmunity. CONCLUSIONS: Human leukocyte antigen gene products may be associated with chronic inflammatory disorders through the unique presentation of “disease-inducing” peptides or the development of a T-cell repertoire prone to autoreactivity and molecular mimicry.

Antineutrophil Cytoplasmic Antibodies in Chronic Idiopathic Intraocular Inflammatory Disease

Antineutrophil cytoplasmic antibodies (ANCA) are found in the sera of patients with Wegener's granulomatosis and other systemic necrotising vasculitides. Antibody levels correlate closely with disease activity so that follow-up of ANCA titres might be helpful in guiding therapy. The authors assessed in a cohort of patients with chronic ocular inflammatory disease ANCA titres prospectively over a two-year period, by an indirect immunofluorescent technique. They found that sera from 10/64 patients (15.6%) stained positive for c-ANCA antibodies, and none stained for p-ANCA. Six c-ANCA positive patients had one or more clinical relapses (range one to three) during this study period. Each relapse correlated with a rise in ANCA titre. The remaining four patients who were found to have persistently low titres of c-ANCA had no clinical relapses. The authors conclude that although c-ANCA is only present in a small proportion of patients with idiopathic chronic intraocular inflammatory disease, the ANCA titre may be used to monitor disease activity in this group of patients. Further study to assess the potential of c-ANCA titres in predicting disease relapse is indicated, which in the future may minimise the side effects of currently used immunosuppressive therapies.

Crohn’s Disease Uveitis: Parasitization of Vitreous Leukocytes by Mollicute-Like Organisms

Crohn's disease (CD) is an idiopathic chronic inflammatory gut disease with frequent extragut inflammatory manifestations in the eyes, orbit, lungs, joints, and skin. A bacterial cause of CD is suspected, but cultivation of a specific pathogen has not been forthcoming. Mollicute-like organisms (MLOs) were recently reported to cause human chronic ocular inflammatory disease. Inoculation of this MLO into mouse eyelids produced chronic progressive granulomatous ocular and orbital inflammatory disease. In addition, MLOs disseminated to produce similar disease in the gut, heart, and lungs. MLOs are noncultivable cell wall-deficient bacterial pathogens. Because they also pass bacteria-retaining 0.450-micron filters, they can be overlooked or confused with viruses. Because MLOs have a characteristic ultrastructural appearance, they can be identified in diseased cells with the use of a transmission electron microscope. MLOs parasitize and destroy leukocytes. They alter the nucleus, replace the cytoplasm, and destroy organelles. MLO-caused disease is treatable by certain antibiotics. This report describes MLO-parasitized vitreous lymphocytes, monocytes, and polymorphonuclear leukocytes from three patients with CD who had chronic uveitis. The results indicate that MLOs probably caused the uveitis of these patients with CD. The gut as the possible source of the MLO is suggested. Rifampin therapy of Crohn's and MLO-caused disease is discussed.