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PubMed2026

ER proteostasis failure in HYOU1 deficiency alters B cells, neutrophils, and interferon signalling.

Hypoxia upregulated 1 (HYOU1) is a stress-inducible ER chaperone. We investigated 2 unrelated patients carrying biallelic HYOU1 variants and presenting with primary immunodeficiency. Patient 1, homozygous for p.Pro444His, displayed failure to thrive, hypoglycemia, B cell lymphopenia, and neutropenia. Patient 2, compound heterozygous for p.Arg262Gln and p.Pro757_Glu758insAla, exhibited recurrent infections, enteropathy, and hypogammaglobulinemia. In Patient 1, while HYOU1 transcription was preserved, the protein was severely reduced. Tunicamycin treatment of dermal fibroblasts showed a blunted unfolded protein response and defective induction of ER stress-responsive genes. Immunophenotyping showed near-absence of circulating B cells, and single-cell RNA sequencing of bone marrow identified an arrest at the pro-B cell stage. Neutrophils displayed hypogranulation and dysregulated IFN- and apoptosis-associated transcriptional signatures, unresponsive to G-CSF. HYOU1 deficiency hence results in ER stress-induced proteostasis failure that simultaneously impairs adaptive immunity through B cell developmental arrest and innate immunity through neutrophil dysfunction and IFN pathway imbalance. This work expands the spectrum of HYOU1 deficiency and further identifies ER proteostasis as a central determinant of immune homeostasis.

Journal Article↗

PubMed2024

Oncogene-induced matrix reorganization controls CD8+ T cell function in the soft-tissue sarcoma microenvironment.

CD8+ T cell dysfunction impedes antitumor immunity in solid cancers, but the underlying mechanisms are diverse and poorly understood. Extracellular matrix (ECM) composition has been linked to impaired T cell migration and enhanced tumor progression; however, impacts of individual ECM molecules on T cell function in the tumor microenvironment (TME) are only beginning to be elucidated. Upstream regulators of aberrant ECM deposition and organization in solid tumors are equally ill-defined. Therefore, we investigated how ECM composition modulates CD8+ T cell function in undifferentiated pleomorphic sarcoma (UPS), an immunologically active desmoplastic tumor. Using an autochthonous murine model of UPS and data from multiple human patient cohorts, we discovered a multifaceted mechanism wherein the transcriptional coactivator YAP1 promotes collagen VI (COLVI) deposition in the UPS TME. In turn, COLVI induces CD8+ T cell dysfunction and immune evasion by remodeling fibrillar collagen and inhibiting T cell autophagic flux. Unexpectedly, collagen I (COLI) opposed COLVI in this setting, promoting CD8+ T cell function and acting as a tumor suppressor. Thus, CD8+ T cell responses in sarcoma depend on oncogene-mediated ECM composition and remodeling.

CD8-Positive T-Lymphocytes↗

PubMed1996

[Job syndrome (hyper-IgE) and hypo-IgA. A rare association of immunodeficiencies].

Job' syndrome and IgA immunodeficiency are a rare dysfunction of the immune system. In this work, we reported a case of a young woman who had recurrent episodes of bacterial infections in the urinary tract and genital, generalized erythematous eczematous patches and stomatitis of oral mucosa and fever. During the hospitalization, laboratory data showed high immunoglobulin IgE and low IgA levels. The T-lymphocyte presented a reduction of CD8+ cells. Tests of granulocyte function have showed a global deficit in the in vitro and in vivo chemotaxis. The correlation between these two clinic conditions is not completely clarified but it is possible to hypothesize that CD8+ lymphocytes produce an inhibition factor of chemotaxis. Job' syndrome is characterized by a selective reduction of CD8+ cells subpopulation which have an immunoregulatory function on the production of IgE by plasmacells. In the ipoIgA, an intrinsic inability of B-IgA cells to proliferate and to differentiate produce a defect in the IgA production. In these two clinic disorders there is an effective dysfunction of immune system. It is possible to hypothesize that an effective defect of CD8+ cells and an immaturity of B-cells may coexist in our patient. That justifies an abnormal production of Ig and a defect in granulocyte chemotaxis.

Adult↗

PubMed1992

Energy transformations in the biosynthesis of the immune system: their relevance to the progression and treatment of AIDS.

Dysfunction of the immune system is observed in diseases where metabolic respiration is inhibited. Anabolites that enhance oxidative phosphorylation will provide the ATP essential for the biosynthesis of the cellular components and antibodies of the immune system. The induction of Coenzyme Q10 has been observed to protect against tumor growth and to enhance viral immunity in experimental animals. In a pilot study in AIDS patients the energy mediating catalyst elicited remarkable improvement. Additional cellular respiratory stimulants are considered as palliative synergists designed to enhance immunity in HIV infection. Competing antagonists to metabolic respiration acting to negate the effect of F delta in mediating optimal immune response to HIV are evaluated.

AIDS Vaccines↗

PubMed1983

Evidence for cell-mediated immunity and specific suppressor T lymphocyte dysfunction in Graves' disease and diabetes mellitus.

Migration inhibition of purified peripheral T lymphocytes in response to pancreatic islet cell antigen or thyroid antigen was used to study cell-mediated immune mechanisms in patients with diabetes mellitus (IDDM) and Graves' disease (GD). In response to islet cell antigen, T lymphocytes of subjects with IDDM for less than 3 yr exhibited migration inhibition, whereas those of normal subjects, noninsulin dependent diabetics, and subjects with IDDM for longer than 3 yr did not. Admixture of T lymphocytes from normal subjects with T lymphocytes from patients with IDDM for less than 3 yr substantially ameliorated the migration inhibition of the IDDM subjects to islet cell antigen. Migration of T lymphocytes from GD subjects was markedly inhibited by thyroid antigen and marginally inhibited by islet cell antigen. Admixture of GD T lymphocytes significantly ameliorated the migration inhibition of IDDM T lymphocytes to islet cell antigen, despite sensitization to thyroid antigen of the GD T lymphocytes. We conclude: 1) sensitization to islet cell antigen in IDDM of recent onset is confirmed; 2) the ability of normal and GD T lymphocytes to ameliorate the migration inhibition of IDDM T lymphocytes strongly suggests correction of deficient suppressor T lymphocyte function; 3) the ability of GD T lymphocytes to ameliorate migration inhibition of IDDM T lymphocytes to islet cell antigen is evidence for an antigen-specific rather than a generalized suppressor T lymphocyte defect in GD; and 4) similarly, the normalization of migration index of GD T lymphocytes in response to thyroid antigen by those IDDM T lymphocytes not sensitized to thyroid antigen is again evidence for an antigen-specific and not a generalized suppressor T lymphocyte defect in IDDM.

Antigens↗

PubMedDate not supplied

Causes of immunosuppression in squamous cell carcinoma of the head and neck.

Numerous dysfunctions of the immune system with prognostic relevance can be found in patients with SCCHN. The role of the different factors affecting the immune system has to be investigated in the future with particular consideration being given to the specific therapy indicated. Varying therapies modifying the immune system are available. It is necessary to clarify whether and how SCCHN patients can benefit from these forms of treatment and how dysfunctions of the immune system can be corrected without causing excessive reactions. From a surgical point of view one has to consider whether immune stimulation or reconstructive measures are indicated in patients with decreased immunity and whether less traumatic procedures with smaller blood loss may have a beneficial effect on the tumor's immunological situation, and therefore on the overall survival of the patient. The terms minimal-invasive or functional surgery may take on a new meaning as biologically-adjusted surgery, biologic preservative reconstructive surgery or biologically functional surgery. In SCCHN not only the radical removal of the primary tumor is of concern, but also the regional lymph nodes and their importance for other lymph nodes, the primary tumor and the immunity of the patient as a whole. These factors have to be taken into consideration in the therapeutic planning for the patient. Therapeutic efforts in SCCHN patients should therefore not only aim at the functional preservation of organs and at plastic reconstructive procedures but also preserve and, by biological immunotherapy, restore the tumor-specific immunity. This may result in better survival rates with better quality of life, even in complicated cases.

Aging↗

PubMed2000

AIDS in an HIV-seronegative Ghanaian woman with intersubtype A/G recombinant HIV-1 infection.

A 29-year-old Ghanaian woman who developed AIDS while being HIV-antibody seronegative was investigated during a collaborative study aimed at the identification of viral causes of a HIV-seronegative AIDS syndrome in West Africa. Plasma was screened with a panel of EIA tests for antibodies to HIV and HIV-1 p24 antigen. Retroviral infection was investigated by detection of reverse transcriptase (RT) activity in plasma, viral RNA amplification and quantification, and virus isolation. Positive amplification products were sequenced and phylogenetic analyses were carried out. Most EIA tests were unable to demonstrate the presence of anti-HIV anti-bodies, whereas confirmatory assays yielded inconclusive results. Retroviral infection was documented by detection of RT activity, HIV-1-specific genomic amplification and virus isolation. This virus was HIV-1 subtype A with an unusual six amino acid insertion in the gp120 V4 loop and with the nef gene of subtype G. The patient's plasma did not react with either autologous or heterologous viral lysates or HIV-1 peptides, whereas antibodies to other viral antigens were present. In conclusion, the Ghanaian patient exhibited a rare subtype A/G recombinant HIV-1 infection with a near absence of a HIV-specific humoral response. The lack of detectable antibody response might be due to either a highly pathogenic, rapidly fatal, HIV-1 infection preventing the development of the typical humoral immune response or to a host-related dysfunction of the immune system. Direct antigenemia or genomic detection of the virus should be undertaken when clinical or biological data suggests an HIV infection in the absence of serological evidence.

Acquired Immunodeficiency Syndrome↗

PubMed1999

The role of immune function in schizophrenia: an overview.

Immune alterations in schizophrenia have been described for decades. However, modern immunological methods and new insights into the highly developed and functionally differentiated immune system allows an integrative view of both, the older and also recent findings of immunological abnormalities in schizophrenia. Both, the unspecific and the specific arm of the immune system seem to be involved in the dysfunction of the immune system in schizophrenia. The unspecific "innate" immune system shows signs of an overactivation in unmedicated schizophrenic patients, as increased monocytes and gamma delta-cells point to. Increased levels of Interleukin-6 (IL-6) and the activation of the IL-6 system in schizophrenia might also be the result of the activation of monocytes/macrophages. On the contrary, several parameters of the specific cellular immune system are blunted, e.g. the decreased T-helper-1 (TH-1) related immune parameters in schizophrenic patients both, in vitro and in vivo. It seems that a TH-1-TH-2 imbalance with a shift to the TH-2 system is associated with schizophrenia. During antipsychotic therapy with neuroleptics, the specific TH-1 related immune answer becomes activated, but also the B-cell system and the antibody production increases.

Antipsychotic Agents↗

PubMed1993

Membrane tumour necrosis factor-alpha is involved in the polyclonal B-cell activation induced by HIV-infected human T cells.

Infection of CD4+ T cells by human immune deficiency virus-1 (HIV-1) causes severe dysfunction of cellular immunity, but paradoxically results in intense polyclonal activation of B cells, possibly accounting for both hypergammaglobulinaemia and frequent development of B-cell malignancies seen in HIV-infected patients. We have reported that human CD4+ T-cell clones infected with HIV in vitro markedly stimulate immunoglobulin synthesis by B cells through a non-cognate, contact-dependent mechanism. We show here that HIV-infected T-cell clones do not express the CD40 ligand (CD40L), a molecule critical for non-cognate B-cell activation, but a small proportion of them do express membrane tumour-necrosis factor (TNF)-alpha. The ability of HIV-infected T-cell clones to induce polyclonal B-cell activation appears to be restricted to TNF-alpha-positive T blasts and is inhibited by antibodies against both TNF-alpha and TNF-alpha receptor. Freshly isolated CD4+ T cells from HIV-infected individuals express TNF-alpha on the cell membrane and induce TNF-alpha-mediated immunoglobulin production by B cells. Thus, membrane TNF-alpha seems to be involved in the polyclonal B-cell activation induced by HIV-infected T cells.

Animals↗

PubMed2006

Musculoskeletal and autoimmune manifestations of HIV, syphilis and tuberculosis.

PURPOSE OF REVIEW: The HIV pandemic continues to increase at an alarming rate, and is the leading cause of death worldwide from a single pathogen. The number of HIV-1-infected individuals currently exceeds 40 million, the majority of whom live in the developing countries of Asia, sub-Saharan Africa and south America. In the past 5 years, there has concurrently been an increase in the reported cases of tuberculosis and primary and secondary syphilis. This review addresses the musculoskeletal and autoimmune manifestations associated with HIV, syphilis and tuberculosis infections or their treatments. RECENT FINDINGS: During HIV infection the immune system becomes dysfunctional because of the coexistence of immunodeficiency and immune hyperactivity, and a disregulated production or activity of cytokines. Some of these mechanisms explain the development of rheumatic manifestations associated with HIV infection. Highly active antiretroviral therapy changes the course of HIV infection and the spectrum of the HIV-associated rheumatic manifestations. New syndromes such as the immune reconstitution inflammatory syndrome have emerged. HIV, tuberculosis and syphilis infections offer special epidemiological, clinical, and therapeutic challenges. SUMMARY: These observations highlight the complexity and multiplicity of the interactions between the pathogen and host that could result in the development of rheumatic manifestations.

Autoimmune Diseases↗

PubMed2000

The immune system and schizophrenia. An integrative view.

Immune alterations in schizophrenia have been described for decades. Modern immunological methods and new insights into the highly developed and functionally differentiated immune system allow an integrative view of both the older and the recent findings of immunological abnormalities in schizophrenia. Both the unspecific and the specific arms of the immune system seem to be involved in the dysfunction of the immune system in schizophrenia. The unspecific, "innate" immune system shows signs of overactivation in unmedicated schizophrenic patients, as indicated by increased monocytes and gamma delta-cells. Increased levels of interleukin-6 (IL-6) and the activation of the IL-6 system in schizophrenia might be the result of the activation of monocytes/macrophages, too. On the other hand, several parameters of the specific cellular immune system are blunted, such as, for example, the decreased T helper-1 (TH-1)-related immune parameters in schizophrenic patients both in vitro and in vivo. It seems that a TH-1-TH-2 imbalance with a shift to the TH-2 system is associated with schizophrenia. During antipsychotic therapy with neuroleptics, the specific TH-1-related immune answer becomes activated, but in addition the B cell system and antibody production increase.

Humans↗

PubMed1984

Effects of long-term treatment of mice with anti-I-J monoclonal antibody and dialyzable leukocyte extract on immune function and lifespan.

In 1969 Walford hypothesized that age-related dysfunctions of the immune system may be involved in the pathogenesis of the lesions and disease of aging. Studies were initiated to test whether immunologic interventions intended to maintain the integrity of the immune system would delay the onset of diseases of aging and prolong lifespan. Adult BC3F1 mice were treated with anti-I-J monoclonal antibody, with human dialyzable leukocyte extract, or with saline once a week for one year. Spleen cells from the mice were then assayed for suppressor, T-helper and B-cell activity. Treatment with dialyzable leukocyte extract decreased the elevated nonspecific suppressor activity. Mice treated with anti-I-J antibody had elevated T-helper cell activity. In another experiment, mice were treated weekly with anti-I-J antibody, dialyzable leukocyte extract, or saline from 18 months of age until natural death. The mice were immunized with avian gammaglobulin at 27 and again at 29 months of age. Both types of immunologic intervention resulted in a greater secondary antibody response than that of the saline-treated control mice. Mice treated with anti-I-J antibody survived longer than did mice of the other two groups. There was a correlation between the magnitude of the secondary response of individual mice and their lifespan. The results provide support for the immunologic theory of aging.

Aging↗

PubMed2003

[Diagnostic and prognostic clinical immunological criteria for evaluating the course of the posttraumatic period in patients with open mandibular fractures].

A total of 136 patients with open mandibular fractures were examined, 53 of these at risk of inflammatory complications in the posttraumatic period. Analysis of the wound cytology, hematological changes, local and system immunity reactions suggest that phagocytosis dysfunction, imbalance of local immunity factors (primarily production, complex formation, and secretion of serum IgA) are significant factors in the development of posttraumatic immune deficiency. Statistical analysis showed clear-cut correlation between local immunity parameters (serum IgA, salivary IgG, levels of circulating immune complexes and medium-weight molecules in the saliva) and hematological values (leukocyte and lymphocyte counts, leukocytic intoxication index, and Rietes coefficient), which confirmed the reliability of prediction of inflammatory complications and necessity of immunocorrection in this patient population.

Adolescent↗

PubMed2004

Intestinal epithelial cell regulation of mucosal inflammation.

The intestinal epithelium serves as one of human's primary interfaces with the outside world. This interface is very heavily colonized with bacteria and yet permits absorption of life-sustaining nutrients while protecting the tissues below from microbial onslaught. Although the gut epithelium had been classically thought to achieve this function primarily by functioning as a passive, albeit highly selective, barrier, research over the last decade has demonstrated that in fact the epithelium plays a very active role in protecting the host from the bacteria that colonize it. As a consequence of its mediation of mucosal immunity, intestinal epithelial dysfunction appears to be central to diseases associated with aberrant gut mucosal immune responses such as inflammatory bowel disease (IBD). This article reviews: (1) how the gut epithelium participates in regulating innate immune inflammatory responses to enteric pathogens, (2) how these responses may regulate the adaptive immune system, (3) mechanisms that may resolve acute inflammation, and (4) how epithelial dysfunction may participate in regulating both the active and chronic phases of IBD.

Bacteria↗

PubMed1998

The Immune Status of Patients with Inflammatory Diseases of the Male Reproductive System.

Immune disorders are very important in pathogenesis of chronic prostatitis. They lead to more prolonged illness and decrease the effect of traditional therapy. 32 healthy men and 51 patients with chronic prostatitis were examined. Combined immunodeficiency was revealed in all patients. T-, B cells count in venous blood decreased, while 0-cells increased. We suggest it is connected to the disturbance of maturation and the differentiation of precursor cells. According to the results of functional tests the early E-rosette-forming cells, the subpopulations of theophylline-sensitive and theophylline-resistant cells decreased. 50.98% of patients had theophylline test inversion. Serum IgG concentration was reduced, while IgA and IgM level were unchanged. It showed that this inflammatory process was not acute. The phagocyte disorders were not strongly marked, but oxygen-dependent destruction of antigen in phagocyte cells was depressed, according to the nitroblue tetrasolium reduction test. The value of the spontaneous nitroblue tetrasolium reduction test was higher compared with the value stimulated with zymosan in 61.54% of patients. In our opinion these alterations are not pathognomonic for disorders of the reproductive organs. They just reflect the immune response to a chronic local inflammatory process. The revealed dysfunctions of the immune system, together with the results of routine examination of the patients with chronic prostatitis, are found to be reasonable. Based on these figures immune system correction therapy should be included in complex treatment of chronic inflammatory diseases of the male reproductive tract.

Journal Article↗

PubMedDate not supplied

Intravenous drug users and the acquired immune deficiency syndrome.

Acquired immune deficiency syndrome (AIDS), a new epidemic disease characterized by dysfunction of cellular immunity, is most common among homosexual and bisexual males with multiple sexual partners and users of intravenous drugs. AIDS appears to be spread by contact with blood products and body fluids. Not only is the heroin user at increased risk of contracting AIDS, but also the occasional recreational drug user who shares a needle and syringe when he or she self-administers cocaine or amphetamines at a party on a weekend. Although precise figures are not available, there may be as many as several million recreational and regular users of cocaine and heroin. Data from a national sample of drug abuse treatment programs indicates that more than 80 percent of all clients seeking treatment, whatever their primary drug of abuse at the time of admission to treatment, have administered drugs to themselves intravenously during the year before treatment. Several hundred thousand treatment episodes occur each year. Data from surveys indicate that drug users entering treatment are well aware of the increased risks associated with AIDS. It is not surprising that treatment staff, also, have expressed concerns about their own susceptibility to the disease. Special education programs for these health workers have been instituted in New York City and have met with success. These programs have provided information and reassurance to treatment providers. At present, no health worker providing direct treatment service to drug abusers with a history of intravenous drug use has contracted AIDS.

Acquired Immunodeficiency Syndrome↗

PubMed1986

Cellular localization of human immunodeficiency virus infection within the brains of acquired immune deficiency syndrome patients.

Dysfunction of the central nervous system (CNS) is a prominent feature of the acquired immune deficiency syndrome (AIDS). Many of these patients have a subacute encephalitis consistent with a viral infection of the CNS. We studied the brains of 12 AIDS patients using in situ hybridization to identify human immunodeficiency virus [HIV, referred to by others as human T-cell lymphotropic virus type III (HTLV-III), lymphadenopathy-associated virus (LAV), AIDS-associated retrovirus (ARV)] nucleic acid sequences and immunocytochemistry to identify viral and cellular proteins. Nine patients had significant HIV infection in the CNS. In all examined brains, the white matter was more severely involved than the grey matter. In most cases the infection was restricted to capillary endothelial cells, mononuclear inflammatory cells, and giant cells. In a single case with severe CNS involvement, a low-level infection was seen in some astrocytes and neurons. These results suggest that CNS dysfunction is due to indirect effects rather than neuronal or glial infection.

Acquired Immunodeficiency Syndrome↗

PubMed1996

Immunomodulation of peripheral lymphocytes by hormones of the hypothalamus-pituitary-thyroid axis.

The aim of this review is to provide a comprehensive examination of the current literature describing the immunoregulatory effects on the peripheral immune system by the hormones that comprise the hypothalamic-pituitary-thyroid (HPT) axis. This article discusses the effects of the HPT axis hormones on the peripheral lymphoid tissues and the immune responses mediated by the cells that comprise these lymphoid tissues. Neuroendocrine dysfunction in the HPT axis, either naturally or experimentally induced, and the resulting immune dysfunction are also discussed. Emphasis in this article is placed on the most recent study findings and those that provide a unique or novel way of evaluating HPT hormone effects on the immune system. Our knowledge of the immunoregulatory effects of the hormones that comprise the HPT axis has grown tremendously in the last 10 years. As can be seen in this review, the immunoregulatory effects of the HPT axis hormones are quite diverse and influence most, if not all, aspects of immune system physiology. The continued exploration of the bidirectional circuitry between the immune and neuroendocrine systems may allow for development of appropriate prophylactic procedures that prevent dysfunction in both systems.

Animals↗