Acute local inflammation causing generalized increased ground substance viscosity: guttate psoriasis, Reiter's syndrome, adjuvant disease, cancer regression

It is known that at sites of acute inflammation there is increased ground substance formation and fibroblast proliferation. There is also increased serum glycoprotein following localized acute inflammation. The author proposes that a severe acute inflammatory response in a localized area of the body induces a generalized increase in ground substance viscosity (generalized ground substance adaptive phenomenon). This would increase host resistance to invasion and heighten the inflammatory response. There are multiple clinical and experimental facts which could be explained by this response. These include guttate psoriasis, pustular psoriasis, pustular bacterid of Andrew's, Reiter's syndrome, and others. This response would include some aspects of adjuvant disease. Increased generalized ground substance viscosity could also explain the beneficial effects of streptococcal cell fractions and streptococcal infections on tumor regression. A number of other clinical observations could be explained. Connective tissue-activating peptide released at the inflammation site could be having a systemic effect. It could be generally beneficial to have generalized increased ground substance viscosity when acute inflammation is occurring in a localized area. A few patients who already have a highly reactive inflammatory level could develop excess inflammation especially at sites of trauma, or preexisting inflammation.     

High viscosity of newborn extracellular matrix is the etiology of erythema toxicum neonatorum: neonatal jaundice?: hyaline membrane disease?

At the time of birth, the fetal ground substance is under the influence of maternal and placental hormones. Hormones are known to exert significant effect on ground substance. The ground substance viscosity that is ideal for intrauterine life is too viscous for the newborn. Sites of minor skin trauma develop swelling, inflammation and pustules. Dilution of tissue fluids causes formation of some of the mediators of inflammation including those responsible for intraepidermal pustule formation. The newborn responds to inflammation with eosinophilic granulocyte. The clinical lesions referred to as erythema toxicum neonatorum are known to localize at pressure sites. The skin lesions correct as maternal and placental hormone influence weakens. The entity occurs in 31 to 72% of white infants. The hormone induced viscosity changes may aid in better understanding some aspects of neonatal physiology; such as jaundice of the neonatal period, the eosinophilic granulocyte inflammatory response of the neonatal period and hyaline membrane disease.     

Cancer resistance, carcinogenesis and ground substance viscosity

Tumor host resistance and promotion are multiple complex simultaneous phenomena. This paper relates only to the effect of ground substance viscosity on tumor host interaction. Tar, anthralin, ultraviolet light, x-ray and arsenic have been widely used to treat inflammatory skin disorders such as psoriasis. They are also well known carcinogens. It is proposed that both the anti-inflammatory effect and part of the carcinogenic effect could occur by decreasing ground substance viscosity and suppressing fibroblasts. Streptococcal infections, chloroquine and pyridoxine deficiency increase inflammatory skin disorders and are known to be beneficial to tumor resistance. It is proposed that both effects could occur because of their effect of increasing ground substance viscosity and, at least with streptococcal infections, by stimulating fibroblasts. Within certain limits, vitamin C has a stimulant effect on fibroblast and ground substance viscosity. Beta carotene is active in stimulating wound healing. Localized edema of the dermal papillae precedes granulocytic inflammation in disorders like psoriasis. Anything that decreases ground substance viscosity will prevent dilution of tissue fluids by decreasing localized edema and thus decrease formation of some mediators of inflammation. Anything that increases ground substance and its viscosity will promote local dilution of tissue fluid. Increasing dilution of tissue fluids promotes the formation of some mediators of inflammation. Tumors commonly secrete hyaluronidase. It is proposed that substances that decrease ground substance viscosity (hyaluronidase-like activity) encourage tumors and substances that increase ground substance viscosity (anti-hyaluronidase-like effect) increase resistance to tumors.     

Non-immunologic enhancement and regression of self-healing squamous cell carcinoma (keratoacanthoma)--ground substance and inflammation

Keratoacanthomas have many characteristics of squamous cell carcinoma and in the past were interpreted as squamous cell carcinomas. It is now known that these lesions spontaneously resolve if left untreated. In man the lesions occur on sunlight damaged areas or areas exposed to tar. Many of the experimental cancers of animals produced by topical carcinogens are keratoacanthomas. Ultraviolet light and tar are known to damage fibroblast and ground substance viscosity. It has recently been proposed that anything that decreases ground substance viscosity would encourage the spread of tumors, by weakening tissue resistance. The rapidly growing keratoacanthoma produces invasive pressure and moves into deeper, less damaged dermis. An inflammatory reaction occurs in the depth of the lesion and a very characteristic granulocytic response occurs. Granulocytes release connective tissue active peptides which stimulate fibroblast and ground substance formation. The fibroblast proliferation is followed by fibrosis and the shrinking and disappearance of the tumor. The characteristic pustule that spurts granulocytes into the depth of the tumor has been experimentally blocked by hyaluronidase and other substances that damage ground substance viscosity. Edema is essential to produce this inflammatory reaction. However, this inflammatory phenomenon occurs vigorously in keratoacanthoma. It is proposed that a keratoacanthoma is a tumor that does not produce hyaluronidase or other substances that decrease ground substance viscosity. It is a deviant cell that can only move through areas of decreased ground substance viscosity. When it reaches tissues of normal viscosity edema and an inflammatory reaction occurs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inflammation spurts: The role of ground substance viscosity

A cyclical phenomenon of spurting polymorphonuclear leukocytes occurs in a number of skin diseases. The phenomenon is easy to observe because the polymorphonuclear leukocytes move into the epidermis and away from the vascular area. It is proposed that repeated spurting of polymorphonuclear leukocytes may be a broad biologic phenomenon. Edema appears essential to initiate the phenomenon by diluting the tissue fluids. The chemicals released by inflammation decrease ground substance viscosity and therefore interfere with dilution of tissue fluids. This stops the mediation of inflammation. The polymorphonuclear leukocytes also release connective tissue activating peptides which lead to increased glycosaminoglycans production and stimulate fibroblast to proliferate. The tissue activating peptides thus restore the viscosity of the ground substance and the cycle can be repeated. What we interpret as chronic inflammation could be the result of this repeated spurting phenomenon.     

Pyridoxine deficiency and antagonism produce increased ground substance viscosity with resulting seborrheic dermatitis and increased tumor resistance

Pyridoxine deficiency and 4'-deoxypyridoxine produce acrodynia in rats and seborrheic dermatitis in man. They also produce tumor inhibition in man and animals. Pyridoxine is extensively involved in metabolism and its relationship to the inhibitor 4'-deoxypyridoxine is complex. Pyridoxine deficiency and antagonism increases ground substance viscosity. This increase the inflammatory reactivity of the skin to produce acrodynia in rats and seborrheic dermatitis in man. The increase in ground substance viscosity would explain the increased resistance to tumors in man and animals. Pyridoxine is important in protein metabolism. The protein moiety of glycosaminoglycans in ground substance is small but plays a major role in tissue viscosity. Pyridoxine deficiency or antagonism by itself does not offer a definitive answer for tumors. Combined with substances that stimulate fibroblast or glycosaminoglycans production it may have a significant additive effect.     

Enhanced inflammatory reactivity in the pathogenesis of spondyloarthropathies

Pathogenesis of seronegative spondyloarthropathies such as ankylosing spondylitis and reactive arthritis is not known. Growing evidence indicates that microbial structures such as Chlamydia antigen and Yersinia antigen are present in the inflamed joints of patients with reactive arthritis. Microbial antigens can activate the host's inflammatory mechanisms. After the activation, the course of inflammation can be postulated to be affected by the host factors responsible for amplification of the inflammatory reaction and elimination of the foreign structures. Thus, the amplification, whether strong, moderate, or weak, may contribute to the degree of inflammatory tissue injury in patients with seronegative spondyloarthropathies. This review will discuss the role of increased inflammatory reactivity in the pathogenesis of HLA-B27 associated spondyloarthropathies, with special reference to reactive arthritis triggered by yersinia enteritis.     

Redox regulation of Fcgamma receptor-mediated phagocytosis: implications for host defense and tissue injury

Recent advances in our understanding of the mechanisms that regulate acute and chronic inflammatory responses have revealed a key role for reactive oxygen intermediates in modulating the activation of neutrophils. Opsonized microbes and immune complexes initiate the oxidative burst by the engagement of receptors for immunoglobulin G, termed Fcgamma receptors. The regulation of phagocytic cell function by oxidant-sensitive signaling pathways optimizes host defense capabilities, but it also amplifies tissue damage. This review will focus on the cross-talk between Fcgamma receptors and reactive oxygen intermediates at sites of inflammation and its role in microbial immunity.     

IL-17 Expression by macrophages is associated with proliferative inflammatory atrophy lesions in prostate cancer patients

Intraprostatic leukocyte function may vary depending on local inflammatory or malignant cell microenvironment. Interleukin (IL)-17 producing cells play key roles in chronic inflammation and autoimmunity. Little is known about the relevance of IL-17 producing cells at sites of prostate tissue inflammation and/or prostate adenocarcinoma. In this study, we analyzed thirty formalin-fixed paraffin-embedded whole-mount radical prostatectomy specimens of prostate cancer patients. Immunohistochemistry was employed to identify IL-17 producing cells in all sites of mononuclear cell accumulation, noting their relationships to areas of prostate cancer, proliferative inflammatory atrophy (PIA), or hyperplastic benign tissue. Levels of IL-17 producing cells were similar in zones of benign prostate tissue and areas of prostate cancer. Pronounced intraluminal and peri-glandular IL-17 producing cell accumulations were identified in the mononuclear cell infiltrates associated with PIA lesions. Glandular and peri-glandular CD68+ macrophages and neutrophils were the predominant IL-17 producing cells in PIA lesions. The accumulation of IL-17 expressing cells in PIA lesions presents direct evidence of an inflammatory microenvironment that may support the development of prostate cancer.     

Cell death and immune privilege

The host response to pathogens involves complex inflammatory responses and immune reactions. While these are central to host defense and vital to clearing infections, they are often accompanied by injury to surrounding tissue. Most organ systems can tolerate these responses without permanent consequences. However, there are sites that limit the spread of inflammation because it can threaten organ function. The most prominent examples of these are the eye, brain, and reproductive organs (testis, ovary), where even minor bouts of inflammation can have long-term consequences for the survival of the organism. In these organs immune responses either do not proceed, or proceed in a manner different from other areas; thus, they are called "immunologically privileged." Here a functioning immune response can be the culprit that leads to disease.     

CELL DEATH AND IMMUNE PRIVILEGE

The host response to pathogens involves complex inflammatory responses and immune reactions. While these are central to host defense and vital to clearing infections, they are often accompanied by injury to surrounding tissue. Most organ systems can tolerate these responses without permanent consequences. However, there are sites that limit the spread of inflammation because it can threaten organ function. The most prominent examples of these are the eye, brain, and reproductive organs (testis, ovary), where even minor bouts of inflammation can have long-term consequences for the survival of the organism. In these organs immune responses either do not proceed, or proceed in a manner different from other areas; thus, they are called "immunologically privileged." Here a functioning immune response can be the culprit that leads to disease.     

Pathophysiology of dermatitis herpetiformis: a model for cutaneous manifestations of gastrointestinal inflammation

Dermatitis herpetiformis (DH) is an autoimmune blistering skin disease in which antigen presentation in the gastrointestinal mucosa results in cutaneous IgA deposition and distinct, neutrophil-driven cutaneous lesions. Our findings suggest that the qualitatively different immune response to gluten in the intestinal mucosa of patients with DH results in minimal clinical symptoms, allowing the continued ingestion of gluten and the eventual development of DH. Our model may provide a new way to understand the pathogenesis of other skin diseases associated with gastrointestinal inflammation such as pyoderma gangrenosum or erythema nodosum, or explain association of seronegative inflammatory arthritis with inflammatory bowel disease.     

Tissue factor expression at the site of inflammation: a cross-talk between inflammation and the blood coagulation system

Recent studies have revealed a close association of the blood coagulation system with inflammation and immune reactions. The products of the cascade reaction of blood coagulation can work as inflammatory mediators or immune modulators, and, vice versa, some inflammatory or immune stimuli are linked to induction of blood coagulation. First, tissue factor (the blood coagulation initiator), the monocyte/macrophage tissue factor expression regulatory factors associated with inflammation and immune reactions, and the assembly of coagulation factors on leukocytes were reviewed. Second, evidence of leukocyte tissue factor expression and subsequent fibrin deposition were demonstrated at sites of infection or allergic reactions, using immunohistochemical staining. Third, the progress in the investigation of thrombin was reviewed from the viewpoint of its effects on inflammation (vascular permeability enhancement, leukocyte chemotaxis, chemical mediator release, etc.) and immune reactions (T-cell proliferation, cytokine production, etc.). The evidence presented here indicates a cross-talk between blood coagulation and inflammatory and immune reactions, suggesting that the products of the clotting reaction (e.g., thrombin) in lesions are real-time markers of inflammatory diseases.     

Immunity, viral pathology and assessment of immune dysfunction in virology and toxicology

General patterns of tissue injury are recognized as characteristic for certain groups of viruses and certain types of host/virus interactions. Acute viral infections, limited in time and space, tend to be accompanied by florid but brief virus replication cycles in tissues and lesions or signs of disease are largely attributable to the cytolytic effects of the virus on host cells. Chronic or persistent viral diseases tend to have low (or difficult to detect) levels of infectious virus on tissues and the lesions tend to be dominated by inflammation, antiviral immune responses and/or host tissue proliferation. At the cellular level, 3 general categories of response to viral infection are recognized: acute cellular swelling with eventual cytolysis, persistent infection, and transformation (neoplastic) infection. Acute cellular swelling may be accompanied by syncytial giant cell formation and/or viral inclusion bodies. Cells persistently infected with viruses though morphologically normal, are increasingly recognized as functionally deficient and may eventually display degenerative change. Transformation to neoplastic growth can be both benign or malignant in cellular expression. In vivo, the initial neutrophilic inflammatory response to virus-induced cellular necrosis is transient and is rapidly superseded by virus-specific inflammation mediated by both humoral and cellular factors and supplemented by the numerous inflammation amplification pathways. Vasculitis, a common but frequently unappreciated event, may produce nonspecific tissue damage via hemorrhage and ischemia in addition to providing a mechanism for egress of inflammatory factors into the areas of virus-induced cellular damage. During the healing phase, repair by substitution (e.g., fibrosis and scarring) or by proliferation of uninfected replacement cells may dominate sites of viral infection.(ABSTRACT TRUNCATED AT 250 WORDS)     

Induction of immunological memory in the skin. Role of local T cell retention

Using an experimental contact sensitivity model in guinea-pigs, evidence is presented that hapten (DNCB or oxazolone) specific T lymphocytes may persist for several months in previous sites of inflammation. Immunological memory, revealed by accelerated contact skin reactions upon retesting with the hapten, was limited to the original contact skin reaction sites. This 'local skin memory' to DNCB or oxazolone could be induced in both specific and non-specific skin inflammatory reactions, provided the animals had been sensitized to the hapten not longer than 2 weeks before. In animals which had been sensitized more than 1 month earlier, local skin memory could be induced if the animals received a booster application of hapten shortly (0-2 days) before primary skin testing. From these results we conclude that recently activated T cells may enter inflammatory sites non-specifically, producing specific local immunological memory. This memory may last several months. Accumulation of hapten specific T cells at inflammatory sites may be important in retest reactivity, in flare-up reactivity and in chronic inflammation.     

Primary breast MALT lymphoma : apropos of one case

A 46-year-old patient was referred for a right mammary nodule associated with a chronic mastopathy. Cytological examination suggested an inflammatory process but frozen sections concluded to carcinoma with lymphoid stroma. Histological examination found characteristic features of MALT lymphoma: reactive lymphoid follicles, lymphoplasmocytoid lymphoid proliferation and lymphoepithelial lesions. Immunohistochemistry and in situ hybridation revealed a monotypic IgGk immunoglobulin. Molecular biology techniques found a rearrangement of IgH locus. Lymphocytic perigalactophoritis was found in the remaining breast tissue. After 33 months, no tumoral recurrence occurred. Primary MALT lymphoma of the breast is exceptional and its histogenesis is unclear. The role of pre-existent inflammatory lesions in the genesis of this tumour is not established. Our observation illustrates the diagnostic difficulty and the usefulness of complementary techniques in this diagnosis. The existence of inflammation close to tumour is interesting to emphasize.     

How mycobacteria take advantage of the weakness in human immune system in the modern world

Tuberculosis (TB) infection remains a global health threat in recent decades partly due to a marked increase in the number of susceptible patients, including those with diabetes mellitus (DM) and who receive biologics. Immunity in TB infection is complex as Mycobacterium tuberculosis (MTB) is a highly adaptive pathogen and may evade the immune defense through various ways. Recent advances in TB immunity have revealed that granulomatous inflammation in TB infection is highly dynamic and the early influx of neutrophils may lead to excessive inflammation and pulmonary cavitation, which provide niches for MTB not only to survive but also to spread to other sites. Furthermore, reactive oxygen species have been found to play a crucial role among pathogenesis of TB infection in diabetics (DM-TB) through regulating inflammasome activation and the production of IL-1β, which in turn modulates the inflammatory network in TB infection, leading to dysfunctional inflammatory responses and tissue remodeling. To understand the exact immunological mechanisms underlying TB infection hence is essential for developing novel adjunctive host-directed therapy (HDT) aiming to alleviate excessive inflammation and tissue destruction and, at the same time, enhance the efficacy of currently available choices of anti-mycobacterial agents. Here we reviewed current epidemiological challenges of global TB control, novel immunological mechanisms underlying dysregulated inflammation in TB infection, especially in DM-TB, and some potential applications of adjunctive HDT in TB treatment.     

Normal wound healing compared to healing within porous Dacron implants

This study examined the hypothesis that healing within porous implants differs from that in normal connective tissue. Special attention was given to extracellular components including collagen, reticular fibers, and ground substance, and to enzymes associated with activated macrophages. Using Dacron velour and the rabbit as host, the healing of normal connective tissue and that of the tissue/implant interface were histologically compared 10 and 28 days postimplantation. The results exhibited significant differences between connective tissue healing, implant capsule formation, and granulation tissue generation. The healing of connective tissue and implant capsule formation were essentially complete at 28 days. However, tissue inside the implant was qualitatively different and did not significantly change between 10 and 28 days. It was characterized by macrophages and giant cells, a predominantly acid mucopolysaccharide ground substance, and qualitatively fewer and less well defined collagen and reticular fibers were observed than in normal wound healing. Thus we conclude that the connective tissue inside Dacron velour does not resemble normal connective tissue after 10 or 28 days of healing. Furthermore, the collagen never fully matures into orderly bundles, a phenomenon which may be related to an altered mucopolysaccharide composition and a diminished reticular network. The lysosomal enzymatic activity of the macrophages and perhaps the giant cells at the tissue/implant interface may be linked to these differences.     

Frequent enrichment for CD8 T cells reactive against common herpes viruses in chronic inflammatory lesions: towards a reassessment of the physiopathological significance of T cell clonal expansions found in autoimmune inflammatory processes

We recently evidenced a dramatic enrichment for T cells reactive against Epstein-Barr virus (EBV) within inflamed joints of two rheumatoid arthritis patients. To assess the generality of this phenomenon and its relevance to autoimmunity, we studied the responses of CD8 T cells from patients with either acute or chronic inflammatory diseases (rheumatoid arthritis: n = 18, ankylosing spondylitis: n = 5, psoriatic arthritis: n = 4, Reiter's syndrome: n = 3, arthrosis: n = 2, uveitis: n = 2, multiple sclerosis: n = 2, encephalitis: n = 1) against viral proteins derived from EBV and another common herpes virus, human cytomegalovirus (CMV). T cell responses against EBV and/or CMV epitopes were frequently observed within CD8 T cells derived from chronic inflammatory lesions, irrespective of their location (knee, eye, brain) and autoimmune features. In most cases, CD8 T cells derived from affected organs yielded stronger anti-viral T cell responses than CD8 T cells derived from patients' PBL, even in chronic inflammatory diseases devoid of autoimmune features or induced by defined bacterial agents. Taken together, these results suggest that the presence of virus-specific T cells within inflamed lesions of patients suffering from autoimmune diseases is a general phenomenon associated with chronic inflammation rather than the initiating cause of the autoimmune process. Since this phenomenon was sometimes associated with long-term T repertoire biases within inflamed lesions, the physiopathological significance of T cell clonal expansions found in a recurrent fashion within chronically inflamed autoimmune lesions should be interpreted with caution.