Immunopathological Abnormalities Research Articles

Regulatory T cells: A potential weapon to combat COVID-19?

Since the end of December 2019, a novel coronavirus SARS‐CoV‐2 began to spread, an infection disease termed COVID‐19. The virus has spread throughout the world in a short period of time, resulting in a pandemic. The number of reported cases in global reached 5 695 596 including 352 460 deaths, as of May 27, 2020. Due to the lack of effective treatment options for COVID‐19, various strategies are being tested. Recently, pathologic studies conducted by two teams in China revealed immunopathologic abnormalities in lung tissue. These results have implications for immunotherapy that could offer a novel therapy strategy for combating lethal viral pneumonia. This review discusses the clinical and pathological features of COVID‐19, the roles of immune cells in pathological processes, and the possible avenues for induction of immunosuppressive T regulatory cells attenuating lung inflammation due to viral infection. It is our hope that these proposals may both be helpful in understanding the novel features of SARS‐CoV‐2 pneumonia as well as providing new immunological strategies for treating the severe sequelae of disease manifestations seen in people infected with SARS‐CoV‐2.

Towards Precision Medicine in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a remarkable condition characterised by diversity amongst its clinical features and immunological abnormalities. In this review, we attempt to capture the major immunological changes linked to the pathophysiology of lupus and discuss the challenge it presents in moving towards the concept of precision medicine. Currently broadly similar types of drugs, e.g., steroids, immunosuppressives, hydroxychloroquine are used to treat many of the diverse clinical features of SLE. We suspect that, as the precise immunopathological abnormalities differ between the various organs/systems in lupus patients, it will be some time before precision medicine can be fully applied to SLE.

Angina Bullosa Hemorrhagica: A Case Report

Angina bullosa hemorrhagica (ABH) is a rare oral mucosal disorder characterized by blood blisters which is not related to hematologic or immunopathologic abnormalities. ABH is most common in middle-aged and elderly people and associated with local trauma, diabetes and long-term use of inhaled steroids. Diagnosis is generally based on reviewing history and clinical presentation and it is important to distinguish it from other serious disorders. Usually, ABH is benign condition which requires no treatment. We present a case of 81-year-old female with ABH.

Pathophysiology of septic shock: From bench to bedside

Our understanding of sepsis and its resultant outcomes remains a paradox. On the one hand, we know more about the pathophysiology of sepsis than ever before. However, this knowledge has not been successfully translated to the bedside, as the vast majority of clinical trials for sepsis have been negative. Yet even in the general absence of positive clinical trials, mortality from sepsis has fallen to its lowest point in history, in large part due to educational campaigns that stress timely antibiotics and hemodynamic support. While additional improvements in outcome will assuredly result from further compliance with evidence based practices, a deeper understanding of the science that underlies the host response in sepsis is critical to the development of novel therapeutics. In this review, we outline immunopathologic abnormalities in sepsis, and then look at potential approaches to therapeutically modulate them. Ultimately, an understanding of the science underlying sepsis should allow the critical care community to utilize precision medicine to combat this devastating disease on an individual basis leading to improved outcomes.

Airflow limitation, asthma, and Chlamydia pneumoniae-specific heat shock protein 60

Chlamydia pneumoniae has been associated with asthma. It has also been suggested that C pneumoniae infection may lead to lung remodeling in a subset of asthmatic patients. Seroreactivity against Chlamydia trachomatis heat shock protein 60 (hsp60), a highly conserved, immunoreactive chaperone protein, is associated with immunopathologic abnormalities, leading to blinding trachoma and tubal infertility. This suggests that the host response to infection may affect chronic inflammatory damage to the eye and the fallopian tubes. The pathogenesis of C trachomatis disease associations is thought to include molecular mimicry (autoimmunity), direct activation of the innate immune response via the CD14/toll-like receptor 4 complex, or both. To study whether airflow limitation in asthma in C pneumoniae-exposed individuals is associated with a specific antibody response to the C pneumoniae hsp60 molecule and not with a genus-specific response to the hsp60 molecule. In a case-control study, we evaluated 138 C pneumoniae-exposed primary care patients (86 adult asthmatic cases and 52 nonasthmatic controls) for seroreactivity against a C pneumoniae-specific hsp60 fragment and against the C trachomatis hsp60 molecule. We analyzed associations with asthma and irreversible lung remodeling as measured by means of postbronchodilator forced expiratory volume in 1 second. Twenty-seven percent of asthmatic patients were C pneumoniae hsp60 seropositive vs 8% of controls (P < .01). Controlling for age, sex, and smoking, C pneumoniae hsp60 seropositivity was associated with lower postbronchodilator forced expiratory volume in 1 second in asthmatic patients (P < .05). No comparable associations were present for C trachomatis hsp60. In individuals with evidence of previous exposure to C pneumoniae infection, a host antibody response against a C pneumoniae hsp60 fragment but not against C trachomatis hsp60 was associated with airflow limitation in adults with asthma.

CD45RA+ immunophenotype in mycosis fungoides: clinical, histological and immunophenotypical features in 22 patients.

Mycosis fungoides (MF) is a cutaneous T-cell lymphoma (CTCL) usually characterized by a T-helper memory phenotype (CD3+, CD4+, CD8-, CD45R0+). Aberrant phenotypes are more commonly seen in the tumor stages. CD45RA expression has so far been documented in only a few cases of CD8+ or TCR gamma delta+ CTCL and in some pagetoid reticulosis cases. Two hundred and fifteen MF patients were immunophenotyped in our laboratory between January 1992 and June 2000 and 22 cases of CD45RA+ MF (8.7%) were identified by immunohistochemical analysis. The majority of these CD45RA+ patients (20/22) showed a patch-plaque stage disease and an indolent clinical course, as expected in early-stage MF. The remaining 2 patients presented with stage IIB and IVA MF, and were characterized by an aggressive clinical course, with systemic spread. The immunohistochemical analysis revealed that CD45RA+ neoplastic cells belonged to the memory compartment, displaying a CD62L-, CD11a+, CD29+ phenotype. Most patients showed aberrant phenotypes, with a loss of T-cell lineage markers and expression of cytotoxic molecules or gamma-delta chain of the T-cell receptor. Our data show that CD45RA+ MF is a rare variant of CTCL and shares with the classic MF cases both the clinical features and disease course, even if it is characterized by a higher incidence of immunopathological abnormalities.

Fluticasone propionate induced alterations to lung function and the immunopathology of asthma over time

BACKGROUNDInhaled corticosteroids are the most widely used treatment for asthma, a disease characterised by both functional and immunopathological abnormalities. This study investigated the relative effects of inhaled corticosteroids on these...

Coincidental cases of primary sclerosing cholangitis and biliary atresia in siblings?

Familial cases of primary sclerosing cholangitis or biliary atresia have been reported, although genetic influences and immunopathological abnormalities in these diseases are considered to be obscure. We report a case of primary sclerosing cholangitis and biliary atresia in siblings with the observation of HLA-DR antigen expression in the abnormal bile duct epithelial cells.

An immunohistological study of desmosomes in Darier's disease and Hailey-Hailey disease

The immunocytochemical distribution of desmosomal components was determined in involved skin from eight patients with Darier's disease, five patients with Hailey-Hailey disease and two patients with transient acantholytic dermatosis as well as skin from four normal controls. Sections were stained using monoclonal antibodies to the desmosomal proteins dp1 and dp2 (desmoplakins) and the desmosomal glycoproteins dg1 (desmoglein), and dg2 and dg3 (desmocollins). There was normal expression of desmosomal proteins and glycoproteins at the periphery of the keratinocytes in the perilesional skin in Darier's disease, in Hailey-Hailey disease and in transient acantholytic dermatosis. In the lesional skin there was reduced expression of desmosomal proteins and glycoproteins in the basaloid 'buds' at the base of the lesions, but there was bright diffuse staining of the acantholytic cells. Focal intracellular staining was detected within many of the acantholytic keratinocytes in Hailey-Hailey disease and within some of these cells in Darier's disease. Suction blisters were used to induce fresh acantholysis in lesional skin in Darier's disease and clinically uninvolved skin in Hailey-Hailey disease. The results indicated that acantholysis precedes the development of intracellular staining. Although there are immunopathological abnormalities in the distribution of desmosomal proteins and glycoproteins in both Darier's disease and Hailey-Hailey disease, the changes are probably secondary to internalization of desmosomal components with breakdown and redistribution of antigens rather than a primary deficiency in the synthesis of these proteins. Focal internalization was more widespread in Hailey-Hailey disease than in Darier's disease and the differences in the distribution of desmosomal components in these diseases confirm that they are distinct entities.

Identification of a Platelet Membrane Glycoprotein as a Falciparum Malaria Sequestration Receptor

Infections with the human malaria parasite Plasmodium falciparum are characterized by sequestration of erythrocytes infected with mature forms of the parasite. Sequestration of infected erythrocytes appears to be critical for survival of the parasite and to mediate immunopathological abnormalities in severe malaria. A leukocyte differentiation antigen (CD36) was previously suggested to have a role in sequestration of malaria-infected erythrocytes. CD36 was purified from platelets, where it is known as GPIV, and was shown to be a receptor for binding of infected erythrocytes. Infected erythrocytes adhered to CD36 immobilized on plastic; purified CD36 exhibited saturable, specific binding to infected erythrocytes; and purified CD36 or antibodies to CD36 inhibited and reversed binding of infected erythrocytes to cultured endothelial cells and melanoma cells in vitro. The portion of the CD36 molecule that reverses cytoadherence may be useful therapeutically for rapid reversal of sequestration in cerebral malaria.

Nutritional therapy for the management of autoimmune diseases

Until recently the study of nutrition has been regarded, at best, as a specialist area of biomedical research but more often has been categorized as fringe faddism. However, nutrition is now beginning to emerge as a credible science and a weighty body of evidence now suggests that the immune system is influenced substantially by the type and quantity of ingested food (for review see Ref. 10). Perhaps the most dramatic and best recognized example of the effects of diet on the immune system is that of protein-calorie malnutrition (12). Particularly common in the third world, afflicted individuals are very much susceptible to infection by all classes of microorganisms. If a balanced diet is made available, normal immune function is restored. Over the last decade data has accumulated from both experimental and clinical studies to convincingly implicate diet in having a substantial role in the manifestation and progression of autoimmune disorders. Autoimmune diseases comprise a diverse group of syndromes of unknown etiology but with genetic, viral, and environmental factors being implicated in their pathogenesis. The majority of investigations, however, have centered on animals systems because of the obvious difficulties associated with human experimentation (11). Without doubt, of greatest significance has been the derivation of several murine models, notably the New Zealand (the NZB and NZB/W) and MRL/ lpr strains which develop, spontaneously, immunopathological abnormalities similar to human autoimmune syndromes (21). Autoimmune diseases comprise a diverse group of syndromes of unknown etiology but with genetic, viral, and environmental factors being implicated in their pathogenesis. Since the observations by Fernandes and colleagues over a decade ago, (8) that either a reduced intake of calories, fat, or protein could delay immune complex nephritis and hemolytic anemia in New Zealand mice, virtually all classes of macroand micronutrients have been shown to be able to modulate a variety of autoimmune disorders.

Immunopathological abnormalities in the normal skin of patients with rheumatoid arthritis in relation to clinical and serological findings: a one year follow up study.

Fifty two patients with seropositive rheumatoid arthritis (RA) were studied over a period of one year to investigate possible relationships among changes of circulating immune complexes (CIC), deposits of immunoglobulins and complement around the cutaneous blood vessels, clinical activity of the disease, and the presence of extra-articular manifestations (EAM). The presence or absence of IgM and C3 in and around the cutaneous blood vessels correlated significantly with the presence or absence of extra-articular features in cross sectional and longitudinal studies. Patients with evidence of these cutaneous immune deposits also had a greater prevalence of CIC as determined by the Clq binding assay (ClqBA) or polyethylene glycol (PEG) assay for IC containing IgM (IgM IC). Although the degree of perivascular mononuclear cell infiltration around the blood vessels in the papillary dermis was related to the patients' clinical state at the initial assessment, it did not correlate with the later changes in the activity of the joint disease or the occurrence of EAM. Thus the deposition of immunoglobulin or complement, or both, seems to be independent of cellular infiltration. The meaning of these cellular infiltrates is not yet fully understood. Our study has shown that many patients with RA who appeared to have only joint disease in fact had subclinical systemic disease as reflected by a positive skin biopsy or CIC. Moreover, the disappearance of IgM deposits from the skin correlated with the disappearance of EAM and improvement of joint disease.

The molecular pathogenesis of bullous pemphigoid

The detection of immunopathologic abnormalities 1 prompted early studies that suggest that bullous pemphigoid is mediated by antibody-dependent complement activation following initiation by an epidermal basement membrane zone antigen. 2 These concepts will not be further considered in this chapter but are reviewed elsewhere (chapter 12) in this volume. Study of the molecular pathogenesis of bullous pemphigoid has been aided by the ease of recognition of each clinical stage in lesional development and by easy access to a complex biologic fluid formed during the inflammatory process. 3 Specimens of lesions at each stage of development from patients were examined for histologic changes by the 1-μm-thick section technique 4 and for immunopathologic abnormalities by direct immunofluorescence. In a single patient, lesions at each stage of development have been examined with the electron microscope for ultrastructural alterations. 5 These studies permitted appreciation of the sequence of pathologic events that must be considered in understanding the molecular pathogenesis of bullous pemphigoid. This chapter considers the pathologic events that characterize the tissue damage observed in bullous pemphigoid. In addition, the potential molecular contribution of cells that participate in the mediation of the inflammatory events characteristic of this unique bullous disease are examined.

Direct and indirect immunofluorescent findings in dermatomyositis.

Three skin biopsies (proximal nailfold, extensor forearm and buttock) and serum samples were studied by direct and indirect immunofluorescence, immunodiffusion and radioimmunoassay techniques in 6 patients with dermatomyositis. A variety of serologic and immunopathologic abnormalities was observed in the patients. Three of 6 patients had antinuclear antibodies (ANA) of a speckled pattern mixed with a peculiar dot pattern. Epidermal intercellular deposits of immunoglobulins were seen in the nailfold biopsies of 2 patients; one of them also had IgG deposits in the cytoplasm of epidermal cells. Forearm and buttock biopsies were negative.

Immune function in severe, active rheumatoid arthritis: a relationship between peripheral blood mononuclear cell proliferation to soluble antigens and mononuclear cell subset profiles.

We have previously reported that patients with active rheumatoid arthritis and depressed in vitro peripheral blood mononuclear cell proliferation to soluble recall antigens (anergic subgroup) improve clinically after repeated short-term leukapheresis, whereas patients with normal responses (nonanergic subgroup) do not. This observation prompted us to examine the mononuclear cell subset profiles in the peripheral blood of anergic and nonanergic seropositive rheumatoid arthritis patients with severe, active, clinically similar disease not taking long-acting anti-rheumatic drugs. In the present study, 42 patients were categorized as anergic (n = 14) or nonanergic (n = 28) on the basis of in vitro peripheral blood mononuclear cell proliferation to soluble recall antigens. The anergic patients had a decreased frequency of OKT4+ mononuclear cells (p less than 0.01), and an increased frequency of OKT8+ cells (p less than 0.02), with a lower OKT4+ :OKT8+ ratio (p less than 0.01) than the nonanergic patients. Anergic patients also had a higher frequency of HLA-DR+ mononuclear cells and HLA-DR+ T cells (p less than 0.001). About 50% of the OKT8+ cells were HLA-DR+, whereas only about 20% of the OKT4+ population expressed HLA-DR antigens. These data suggest that the decreased lymphocyte function described in the anergic patient subgroup is associated with characteristic peripheral blood mononuclear cell subset profiles. Moreover, when considered in the context of other data indicating that anergic patients have characteristic synovial immunopathologic abnormalities, these data provide insight into potential pathogenic mechanisms of this disorder.

Chronic graft-versus-host disease in the rat radiation chimera. III. Immunology and immunopathology in rapidly induced models.

Although chronic graft-versus-host disease (GVHD) frequently develops in the long-term rat radiation chimera, we present three additional models in which a histologically similar disease is rapidly induced. These include adoptive transfer of spleen and bone marrow from rats with spontaneous chronic GVHD into lethally irradiated rats of the primary host strain; sublethal irradiation of stable chimeras followed by a booster transplant; and transfer of spleen cells of chimeras recovering from acute GVHD into second-party (primary recipient strain) or third-party hosts. Some immunopathologic and immune abnormalities associated with spontaneous chronic GVHD were not observed in one or more of the induced models. Thus, IgM deposition in the skin, antinuclear antibodies, and vasculitis appear to be paraphenomena. On the other hand, lymphoid hypocellularity of the thymic medulla, immaturity of splenic follicles, and nonspecific suppressor cells were consistently present in the long term chimeras, and in all models. These abnormalities therefore may be pathogenetically important, or closely related to the development of chronic GVHD.