Mucocutaneous Inflammation Research Articles

Genetic variants in the HLA-G region are associated with Kawasaki disease

Kawasaki disease is an acute, self-limited vasculitis of infants and children, manifest as fever and signs of mucocutaneous inflammation. Treatment with high-dose immunoglobulin reduces systemic inflammation and prevents coronary artery lesions in Kawasaki disease. In this study, we investigated the possible association of the major histocompatibililty complex (MHC) region for the susceptibility to Kawasaki disease using an MHC panel of 2360 single nucleotide polymorphism (SNP) markers. Analysis of data obtained from screening MHC-specific SNP chips with 48 case and 90 control subjects revealed five candidate loci with significance levels of uncorrected p < 0.01. However, only one candidate locus (HLA-G) was confirmed to have a significant association with Kawasaki disease (rs2523790, odds ratio [OR] = 3.00, 95% confidence interval [95% CI] = 1.14–7.91, uncorrected p = 0.0263) in the replication study using 44 new case subjects and the previous 90 controls. In the fine mapping of the HLA-G locus, in particular, a nonsynonymous SNP (C/A) of the HLA-G gene (rs12722477, Leu134Ile) was significantly associated with Kawasaki disease (OR = 3.23, 95% CI = 1.12–9.32). A subgroup analysis showed that this association was more apparent in patients with coronary artery aneurysms (OR = 4.02, 95% CI = 1.23–13.19). Therefore, our results indicate that HLA-G may play a crucial role for the susceptibility to Kawasaki disease.

Valvular and coronary heart disease in systemic inflammatory diseases

Systemic lupus erythematosus (SLE), primary antiphospholipid syndrome (PAPS), rheumatoid arthritis (RA), ankylosing spondylitis (AKS), and scleroderma are immune mediated inflammatory diseases that manifest predominantly with symptoms and signs of musculoskeletal...

Chronic inflammation is etiology of extrinsic aging

Skin care regimens using active ingredients that are recommended by physicians who treat mucocutaneous conditions including aging should become more focused on reversing and preventing chronic inflammation. This adjustment of therapeutic and preventive strategies is necessary because chronic inflammation appears strongly linked to many preventable and treatable skin diseases and conditions such as visible skin aging. Mucocutaneous inflammation as the final common pathway of many systemic and mucocutaneous diseases including extrinsic aging has been established at the molecular and cellular levels. The corollary to this strategy includes inhibition of primary activators of mucocutaneous inflammation such as stratum corneum permeability barrier disruption, blocking any pro-inflammatory environmental insult such as ultraviolet radiation, and quenching tissue responses to these insults. This review will present the scientific rationale substantiating the conclusion that chronic inflammation is the common denominator in many mucocutaneous pathophysiologic processes including extrinsic skin aging.

VALVULAR DISEASE ASSOCIATED WITH SYSTEMIC ILLNESS

The connective tissue diseases are immune-mediated inflammatory diseases that manifest predominantly with symptoms and signs of musculoskeletal and mucocutaneous inflammation. They frequently affect the heart valves, pericardium, and myocardium. In patients with AKS, the aortic root and conduction system are also frequently involved. Echocardiographic series in these patients have demonstrated that valvular disease is highly prevalent and associated with substantial morbidity and mortality (Table 1). The prevalence rates of clinically detected valvular disease, however, are either unknown or low. This discrepancy is related to lack of awareness, overshadowing of the cardiovascular manifestations by the inflammatory symptoms and signs of the musculoskeletal system, lack of systematic application of the history and cardiovascular physical examination, and high sensitivity of echocardiography for detecting subclinical abnormalities. Several valvular abnormalities have been identified as unique to a specific disease. Libman-Sacks vegetations, valve nodules, and subaortic bump are characteristic of SLE, RA, and AKS (see Table 1). The valvular complications and respective therapy are similar to those of other causes of valvular disease; however, the associated morbidity and mortality of these complications in these patients are high. The worse prognosis of valvular disease in these patients is related to the chronicity and debilitating nature of their illness, their high prevalence of multisystem disease, and immunosuppression. These factors underscore the importance of early recognition, prevention of complications, and proper clinical or echocardiographic follow-up. The distinctive echocardiographic characteristics of the valve abnormalities associated with the connective tissue diseases may allow their differentiation from other common valvulopathies, such as infective endocarditis, rheumatic valvular disease, and degenerative valvular disease (Table 2). Despite the clinical and prognostic implications of valvular disease associated with the connective tissue diseases, incomplete data are available about pathogenesis, relation to clinical features of the primary disease, evolution, and effect of steroid or cytotoxic therapy. Echocardiography, especially TEE, has the potential to redefine the prevalence rates and to characterize better the valve abnormalities associated with these conditions. Finally, future large cross-sectional and longitudinal studies using clinical and echocardiographic data may help to define better the presence, evolution, and therapy of the valvular disease associated with the connective tissue diseases.

The potential role of bacterial superantigens in the pathogenesis of Kawasaki syndrome.

Kawasaki syndrome is an acute multisystem vasculitis of infancy and early childhood associated with high fever, mucocutaneous inflammation, and the development of coronary artery abnormalities. Despite the widely held belief that Kawasaki syndrome is an infectious disease, investigations have failed to identify a causal organism. Previous studies have demonstrated that this illness is associated with marked activation of monocyte/macrophages and the selective expansion of V beta 2-, less so, of V beta 8.1/8.2-expressing T cells in the peripheral blood from Kawasaki syndrome patients during the acute phase of their illness. These immunologic features are characteristic of diseases that are caused by bacterial toxins which act as superantigens. Staphylococcal enterotoxins and streptococcal exotoxins are prototypic superantigens which stimulate large populations of T cells expressing particular T-cell receptor beta-chain variable (V beta) gene segments. Using the V beta 2+ T-cell expansion as an "immunologic footprint" for a superantigen, we have extended these observations to the identification and isolation of a novel clone of toxic shock syndrome toxin-1-producing Staphylococcus aureus in the majority of patients with Kawasaki syndrome and streptococcal pyrogenic exotoxin B/streptococcal pyrogenic exotoxin C-producing streptococci in a minority of Kawasaki syndrome patients. Toxic shock syndrome toxin-1, streptococcal pyrogenic exotoxin B, and streptococcal pyrogenic exotoxin C are known to stimulate V beta 2+ T cells. These observations support the hypothesis that the activation of V beta 2+ T cells during the acute phase of Kawasaki syndrome is caused by bacterial superantigen(s).

Kawasaki Disease and Its Cardiac Sequelae

In 1967, Tomisaku Kawasaki described a syndrome of mucocutaneous inflammation in 50 Japanese children. Seven years later, he reported his experience in English, emphasizing that 1% to 2% of affected children died of cardiac failure. Since then, Kawasaki disease has been described worldwide in children of all racial groups and has been recognized as a leading cause of acquired heart disease among children in the United States (Figure 1). The disease affects mostly toddlers; about 80% of patients are less than five years old, and only rare cases are seen in adolescents over age 15. Intravenous gamma globulin has recently been demonstrated to reduce systemic inflammation and the prevalence of coronary artery aneurysms in patients with Kawasaki disease. The treatment, however, is effective only if administered early in the illness. Hence, prompt and accurate diagnosis is essential. The following cases offer a context in which to discuss some of the clinical issues surrounding Kawasaki disease.

Gamma globulin re-treatment in Kawasaki disease

We retrospectively reviewed the effects of intravenous gamma-globulin (IVGG) re-treatment of 13 children with Kawasaki disease and persistent or recrudescent fever. Fever and mucocutaneous inflammation resolved within 48 hours in nine patients; fever abated in two other children after a third course of IVGG. We conclude that IVGG re-treatment of Kawasaki disease appears to be safe and may improve the clinical course.

Intravenous gamma globulin inhibits immunoglobulin production and cytokine mRNA expression in human peripheral blood mononuclear cells

We retrospectively reviewed the effects of intravenous γ-globulin (IVGG) re-treatment of 13 children with Kawasaki disease and persistent or recrudescent fever. Fever and mucocutaneous inflammation resolved within 48 hours in nine patients; fever abated in two other children after a third course of IVGG. We conclude that IVGG re-treatment of Kawasaki disease appears to be safe and may improve the clinical course.

Therapy of the Spondyloarthropathies

The key to successful therapy for patients with ankylosing spondylitis is a lifelong, carefully devised, and well-instructed exercise program. This program is designed to maintain maximum range of motion within the spine, and the costovertebral and girdle joints, thereby preventing the tendency to flexion contractures and loss of height. The exercise program frequency requires long-term concomitant therapy with nonsteroidal anti-inflammatory drugs, partly to relieve the painful perispinal muscle spasm which frequently inhibits the exercise movements. The drugs are not known to alter the natural history of the inflammatory lesion. Local measures directed at ocular, urethral, and mucocutaneous inflammation may be symptomatically beneficial. These simple therapeutic principles ensure a good functional prognosis in the vast majority of patients with spondylitis.