Immune dysfunctions and activation of natural killer cells in human IL-2 and IL-2/IL-2 receptor L-chain transgenic mice.
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Animals↗
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Infections in the diabetic patient: the role of immune dysfunction and pathogen virulence factors.
It is a common belief that certain infections occur more frequently in patients with diabetes mellitus than in nondiabetics. In some infections, poor diabetic control is strongly linked. Diabetics comprise 50%-70% of all patients who undergo nontraumatic foot or leg amputations, the overwhelming majority of which are necessitated by infection and necrosis of soft tissue and/or bone. Imputed host defense abnormalities include defective immune responses (e.g., white blood cell function, granuloma formation), peripheral neuropathies, impaired distal arterial supply, and problems in "control" of the diabetic state eventuating in catabolic metabolism. Increased bacterial translocation as a source of the causative bacteria is another potential entry site. Possible virulence factors of the invading organisms include polymicrobial synergism, glycocalyx formation, and inoculum size. Attention to the principles of preventive education, vascular evaluation, diabetes management, and adequate debridement maximize healing potential.
Communicable Diseases↗
Use of the integrated steady state rate equation to investigate product inhibition of human red cell adenosine deaminase and its relevance to immune dysfunction.
The analysis of progress curves using the integrated rate equation was applied to the adenosine deaminase-catalyzed conversion of adenosine to inosine. Adenosine deaminase was purified from human red blood cells of phenotypes ADA 1, ADA 2, and ADA 2-1. For all three types, no measurable product inhibition by inosine was observed. These results do not confirm the hypothesis that inosine accumulation in purine nucleoside phosphorylase deficiency causes adenosine deaminase inhibition, resulting in a common mechanism for the immune defects related to these two enzyme deficiencies.
Adenosine Deaminase↗
Epidermodysplasia verruciformis induced by a new human papillomavirus (HPV-8). Report of a case without immune dysfunction. Effect of treatment with an aromatic retinoid.
A new case of epidermodysplasia verruciformis (EV) is reported in a 35-year-old man characterized by multiple common warts, flat warts, psoriasis-form lesions, and pityriasis-versicolor-(PV) like lesions. There was no familial history, no mental retardation, and no malignant changes. Human papilloma virus type 8 was identified in PV-like lesions. Immunologic studies detected no abnormalities: Delayed skin tests, DNCB sensitization, levels of immunoglobulins, complement components, circulating immune complexes, number of circulating lymphocytes, lymphocyte membrane markers, proliferative responses to mitogens, Ts activity, and Ts subpopulations as detected by monoclonal antibodies were considered to be within normal limits. A treatment with a retinoid aromatic (RO 10-9359) improved the clinical status of the patient and did not modify the immune parameters.
Adult↗
Role of nutrition in the management of malnutrition and immune dysfunction of trauma.
Current nutrition support improves patient outcome in trauma patients. It appears to do so by limiting the adverse effects of specific nutrient or generalized nutrient deficiencies. Immunosuppression, however, continues as a significant clinical problem. This immunosuppression appears to be part of the inflammatory response that accompanies trauma, and in part, to represent the need for conditional nutrients in this setting. Three nutrients that are being evaluated include arginine, uracil as ribonucleic acid and omega-3 polyunsaturated fatty acids. Animal studies report improved immune function. Early clinical trials are reporting improved immune function and patient outcomes.
Animals↗
Metabolic correlates of immune dysfunction in malnourished children.
Mononuclear cells of malnourished children contain diminished activity of phosphoglycerate kinase and pyruvate kinase (PK). The PK activity of these cells correlates well with the percentage of circulating thymus-derived lymphocytes (T-cells). Phytohemagglutinin causes an immediate increase in PK activity of mononuclear cells of malnourished patients. The correlation of PK activity with T-cells and the response of PK activity to phytohemagglutinin are in distinct contrast to observed perturbations of neonatal mononuclear cell metabolism. The relationship of the metabolic alterations to the pathophysiology of the immune system in malnutrition has not yet been defined.
Adolescent↗
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)
Animals↗
Spike protein-induced VSIR-ISX signaling disrupts metabolic homeostasis and promotes COVID-19-related immune dysfunction.
COVID-19 has caused millions of deaths worldwide since 2019. Vaccination has reduced both transmission and disease severity. However, emerging viral variants have weakened vaccine effectiveness, highlighting the need for new antiviral therapies. This study examines how the SARS-CoV-2-Spike protein (SARS-2-S) induces the VSIR-ISX signaling pathway, leading to metabolic disturbances that may worsen disease progression. Using RNA sequencing, we found that SARS-2-S expression in pulmonary cells activates genes involved in tryptophan and arachidonic acid (AA) metabolism, altering bioactive mediators like kynurenine and prostanoids, which are crucial for inflammation and immune responses. Mechanistically, the ACE2-MYD88 pathway, activated by SARS-2-S, enhances the VSIR-ISX axis through NF-κB signaling, driving these metabolic disruptions. Chromatin immunoprecipitation and genome sequencing revealed that ISX, activated via VSIR-MAPK signaling, upregulates enzymes involved in AA metabolism by binding directly to their gene promoters. Notably, disrupting the VSIR-ISX axis using shRNA interference or NF-κB inhibitors effectively mitigated these metabolic disturbances. Our findings suggest that the VSIR-ISX pathway could be a promising therapeutic target for treating COVID-19 by addressing virus-induced metabolic disruptions.
Humans↗
Determinants of the ability of malignant fibroma virus to induce immune dysfunction and tumor dissemination in vivo.
The relationship of virus-induced immunological dysfunction and tumor dissemination was studied using two related tumor-causing leporipoxviruses: malignant fibroma virus (MV) and Shope fibroma virus (SFV). Recombinant viruses, produced by transferring MV's 10.7 kb BamHI C fragment to SFV, replicate in lymphocytes and suppress lymphocyte function in vitro. Those recombinants that replicate in lymphocytes and suppress lymphocyte function in vitro share about 3.5 kb from MV's C fragment. Some recombinants mimic MV in producing immune suppression and disseminated virus infection in vivo. Other recombinants, even some that are highly immunosuppressive in vitro (e.g. R71), only variably induce immune suppression in vivo, and do not cause disseminated disease. A segment of DNA from MV that transfers to Shope fibroma virus almost all of MV's virulence in vivo was identified.
Animals↗
Accumulation of hyporesponsive, calcium extruding memory T cells as a key feature of age-dependent immune dysfunction.
In this review I propose a hypothesis with a number of testable predictions: that the age-dependent decline in T lymphocyte function is largely the result of the accumulation of memory T lymphocytes with over-active plasma membrane calcium pumps. This idea is consistent with much, though not all, of the currently available data. I will start by presenting the evidence that suggested and most clearly supports this idea, then discuss apparently contrary data (some of it still difficult to reconcile with the model), and lastly consider the implications of the model for our understanding of late life development of the T cell immune system.
Aging↗
Sinus histiocytosis with massive lymphadenopathy: a spectrum of disease associated with immune dysfunction.
A detailed immunologic study of three cases of sinus histiocytosis with massive lymphadenopathy (SHML) was performed to better characterize this rare disorder. One patient had prominent cervical lymphadenopathy that regressed spontaneously, whereas the other two patients had persistent cervical lymphadenopathy and recurrent infections. The first patient was otherwise healthy and had normal immunologic studies. One of the latter patients had a relative increase in blood B cells, a decreased level of serum immunoglobulin A (IgA), decreased blood lymphocyte mitogenic responses to multiple mitogens (37-42% of controls), and cutaneous anergy. The other patient with persistent disease also had a relative increase in blood B cells, polyclonal hypergammaglobulinemia, and circulating immune complexes, as well as decreased blood T cells and markedly decreased blood lymphocyte responses to mitogens (12-37% of controls). Immunohistochemical stains of the lymph nodes of the three patients revealed a characteristic phenotype for the sinus histiocytes: S-100 protein, 3/3; CD14 (Leu M3) 3/3; CD11c (Leu M5), 1/1; CD71 (OKT9), 3/3; CD4 (Leu 3a), 2/3; CD1a (OKT6), 1/3; alpha-1-antitrypsin, 3/3; alpha-1-antichymotrypsin, 3/3; CD35 (C3b), 1/1; CD11b (Mo1), 0/3; CD15 (Leu M1), 0/3; HLA-DR, 0/3; and lysozyme, 0/3. This phenotype suggests that the cells of SHML have features of both the Langerhans/interdigitating cell and mononuclear phagocyte lineages. Emperipolesis by the histiocytes of B cells, T cells, and natural killer cells was demonstrated by a double-staining technique. Our findings indicate that patients with SHML may have a variably expressed immunodeficiency that predisposes them to recurrent infections.
Child↗
The development of immunotoxins for the therapy of cancer, AIDS, and immune dysfunctions.
Immunotoxins (ITs) consist of cell-reactive ligands coupled to toxins or their toxic subunits. The ligands are usually antibodies, hormones, or growth factors and the toxins are of bacterial or plant origin. In the case of the plant toxin, ricin, its structure consists of a ribosome-inactivating A chain of 32 Kd linked by a disulfide bond to a galactose-specific lectin (B chain) of approximately 30 Kd. The A and B chains of ricin can be separated following reduction and the A chain can then be purified and chemically linked to different ligands to generate a cell-reactive conjugate. Studies using A chain-containing ITs to specifically delete tumor cells, or regulatory cells of the immune system began a decade ago. Initial in vitro experiments were successful and led to further experiments in vivo. However, in vivo studies carried out over the past five years in both animals and humans have demonstrated that the efficacy of ITs or conjugates in vivo is often poor due to problems involving instability of the conjugate, inferior potency, inaccessibility of tumor cells, nonspecific binding to cells other than the target cells, and the survival of antigen-negative mutants. In addition, immune responses against both the ligand and the A chain are usually elicited, precluding repeated therapy. During the past several years, there have been attempts to solve these problems and thereby develop more effective ITs. By analogy with conventional chemotherapeutic agents, it could be predicted that immunotoxins will require many years of study to optimize their construction and therapeutic regimens.(ABSTRACT TRUNCATED AT 250 WORDS)
Acquired Immunodeficiency Syndrome↗
Common epitope in human immunodeficiency virus (HIV) I-GP41 and HLA class II elicits immunosuppressive autoantibodies capable of contributing to immune dysfunction in HIV I-infected individuals.
We previously reported the identification of highly conserved homologous regions located in the carboxy terminus of the HIV I gp41-envelope (aa 837-844), and the amino-terminal of the beta chain of all human HLA class II antigens (aa 19-25). Murine monoclonal antibodies, raised against synthetic peptides from these homologous regions, bound not only to the isolated peptides, but also to the native gp160 and class II molecules. In this study one-third of sera from HIV I-infected individuals, at different disease stages, were found to react with both the gp41 and class II-derived peptides. These sera also reacted with "native" HLA class II molecules. The potential affects of such autoantibodies on normal immune functions were examined. It was found that in the presence of class II-cross-reactive (but not control) sera, the proliferative responses of normal CD4+ T cells to tetanus toxoid and allogeneic stimuli were markedly decreased. In addition, these sera could eliminate class II-bearing cells by antibody dependent cellular cytotoxicity. Similar affects were seen with affinity-purified IgG antibodies from patients' sera. Thus, the "molecular mimicry" between HIV I and HLA class II antigens, may lead to the generation of autoantibodies in HIV I-infected individuals that may contribute to the early functional impairment of CD4+ T cell observed in many HIV I-infected individuals.
Acquired Immunodeficiency Syndrome↗
Malnutrition and immune dysfunction in patients infected with human immunodeficiency virus.
STUDY OBJECTIVE: To determine forms of malnutrition and basal metabolism at different stages of immunological impairment in clinically stable patients infected with Human Immunodeficiency Virus (HIV). DESIGN: Cross sectional study. SETTING: 53 outpatients with HIV-infection classified according to the Walter Reed staging system (WR1 to WR6). MEASUREMENTS AND MAIN RESULTS: 87% of the patients showed some evidence of malnutrition. Reduced body weight was found in 53%, 68% and 25% had decreases in fat and body cell mass, 17% had visceral protein deficiency, whereas extracellular mass and serum triglyceride concentrations were increased in 58% and 30%, respectively. Reduced serum albumin and transferrin closely paralleled immunological depression, whereas alterations in body composition were manifest early during HIV-infection (WR3) and remained unchanged during the transition to the Acquired Immune Deficiency Syndrome itself. Resting metabolic rate increased from WR1 to WR3; it remained within the expected range during later stages (WR4-WR6), but was not appropriately reduced in response to the loss in body cell mass. CONCLUSIONS: HIV-infected patients display both, calorie and protein malnutrition. Immunological depression was independent of loss of body mass, but was closely associated to decreases in serum albumin values. Nutritional assessment and intervention should therefore be performed at an early stage of HIV-infection.
Adult↗
Immunotoxicology: environmental contamination by polybrominated biphenyls and immune dysfunction among residents of the State of Michigan.
In 1973, inadvertent contamination occurred in a special farm feed supplement for lactating cows. Polybrominated biphenyls (PBBs) were used in place of magnesium oxide resulting in serious harm to farm animals, including cattle, chickens, geese, ducks. Farm families, accustomed to eating their own products, were most heavily exposed. To study the impact of PBBs, 336 adult Michigan farm residents, 117 general consumers for comparison, 75 dairy farm residents in Wisconsin, who had not eaten PBB-contaminated food, were examined, as were 79 healthy subjects in New York City. Abnormalities in the Michigan groups included hypergammaglobulinemia, exaggerated hypersensitive response to streptococci, significant decrease in absolute numbers and percentage of T and B-lymphocytes, and increased number of lymphocytes with no detectable surface markers ("null cells"). Significant reduction of in vitro immune function was noted in 20-25% of the Michigan farm residents who had eaten food containing PBB. The decreased immune function detected among the PBB-exposed farm residents tended to affect families as a unit and was independent of exposed individuals' age or sex, pointing against the possibility of genetic predisposition.
Agricultural Workers' Diseases↗
Immune dysfunction in rats fed a diet deficient in copper.
Rat pups maintained on copper (Cu)-adequate (6ppm), Cu-deficient (2 ppm) or Cu-depleted (0 ppm) diets from parturition were killed at 8-wk. Liver Cu and serum-ceruloplasmin levels confirmed that on the 0- and 2-ppm diets, a Cu-deficient state was induced. Although body weight was unaffected by the deficiency, the liver, heart, and thymus weights (% body weight) were altered. Hepatomegaly occurred in females fed 0-ppm Cu and males fed 2-ppm Cu. Heart weights increased in both sexes fed 0-ppm Cu. Thymus weights decreased in male rats fed 0-ppm Cu. Antibody titers and natural killer-cell cytotoxicity were markedly suppressed in the animals fed 0-ppm Cu. Male rats given 2-ppm Cu showed reduced antibody titer. Delayed-type hypersensitivity and prostaglandin E2 levels were not significantly affected. These studies suggest that certain components of the immune system are Cu dependent.
Animals↗
Vitamin D dependent rickets type II with myelofibrosis and immune dysfunction.
We present a new patient with vitamin D dependent rickets type II. A 20-month-old Arabian boy whose parents are first cousins showed florid rickets, myelofibrosis and recurrent septicaemia. In addition to absent specific binding for 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). 25-Hydroxyvitamin D3-24-hydroxylase activity could not be induced in cultured fibroblasts. The patient did not respond to 99 micrograms 1,25(OH)2D3 per day, but skeletal and haematological abnormalities improved with daily infusion of 100 mg/kg calcium, as serum parathyroid hormone levels fell to normal values. At the age of 7 years, he died from pneumonia. The improvement of haematological abnormalities with calcium infusions but not with 1.25(OH)2D3 suggests a pathogenetic relationship of myelofibrosis and hyperparathyroidism. Having anti-lipid A IgM antibody titres up to 1:10.000 after Gram negative septicaemias, the patient never produced corresponding IgG antibodies. His neutrophil chemotaxis was persistently reduced to 57% +/- 3% of age-matched controls (P less than 0.028). The patient showed two pathological immune functions considered to contribute to the well-known susceptibility to infection in rickets.
Calcium↗
Evidence that prior immune dysfunction predisposes to human immunodeficiency virus infection in homosexual men.
To investigate the role of host susceptibility to HIV-1 infection, we studied subsequent seroconversion in 161 individuals, initially seronegative to HIV-1, who underwent skin testing for cutaneous anergy at an index visit within a prospective study of homosexual men. There were 23 seroconversions in these men by 45 months following the skin testing, yielding a crude rate of seroconversion of 14.3%. While results of purified protein derivative (PPD), Candida, and Trichophyton skin tests were not associated with subsequent course, anergy to dinitrochlorobenzene (DNCB) was predictive of subsequent seroconversion. Kaplan-Meier estimates for the risk of seroconversion during 45 months of follow-up in those men initially anergic and reactive to DNCB were 28.9 and 11.1%, respectively, yielding a relative risk of 2.6 (p = 0.006). The estimated relative risk was stable with adjustment by Cox regression for annual number of male sexual partners and frequency of receptive anal intercourse, and was not sensitive to various changes in the definition of seroconversion time and of eligibility criteria. These data suggest that an impaired host immune status may be associated with an increased risk of HIV-1 infection that is independent of risk of exposure to the virus, supporting earlier speculations that HIV-1 may itself be opportunistic. The notion of varying host susceptibility to infection, at least with regard to sexual transmission in homosexual men, may help to explain the frequent observation of individuals who have been repeatedly exposed to the virus and yet have remained uninfected.
Acquired Immunodeficiency Syndrome↗