Aberrant Disgust Responses and Immune Reactivity in Cocaine-Dependent Men

Background: Infectious diseases are the most common and cost-intensive health complications associated with drug addiction. There is wide belief that drug-dependent individuals expose themselves more regularly to disease-related pathogens through risky behaviors such as sharing pipes and needles, thereby increasing their risk for contracting an infectious disease. However, evidence is emerging indicating that not only lifestyle but also the immunomodulatory effects of addictive drugs, such as cocaine, may account for their high infection risk. As feelings of disgust are thought to be an important psychological mechanism in avoiding the exposure to pathogens, we sought to investigate behavioral, physiological, and immune responses to disgust-evoking cues in both cocaine-dependent and healthy men. Methods: All participants (N = 61) were exposed to neutral and disgust-evoking photographs depicting food and nonfood images while response accuracy, latency, and skin conductivity were recorded. Saliva samples were collected before and after exposure to neutral and disgusting images, respectively. Attitudes toward disgust and hygiene behaviors were assessed using questionnaire measures. Results: Response times to disgust-evoking photographs were prolonged in all participants, and specifically in cocaine-dependent individuals. While viewing the disgusting images, cocaine-dependent individuals exhibited aberrant skin conductivity and increased the secretion of the salivary cytokine interleukin-6 relative to control participants. Conclusion: Our data provide evidence of a hypersensitivity to disgusting stimuli in cocaine-dependent individuals, possibly reflecting conditioned responses to noningestive sources of infection. Coupled with a lack of interoception of bodily signals, aberrant disgust responses might lead to increased infection susceptibility in affected individuals

Interferon gamma replacement as salvage therapy in chronic pulmonary aspergillosis: effects on frequency of acute exacerbation and all-cause hospital admission.

Chronic pulmonary aspergillosis (CPA) is often poorly responsive to antifungal treatment; secondary infections increase morbidity/mortality, particularly in progressive cases. Interferon gamma (IFNγ) has been implicated in not only Aspergillus control but also bacterial clearance. Clinical notes of patients with CPA treated with IFNγ (2011-2018) were retrospectively hand-searched. In patients treated for >12 months (n=20), the frequency of acute exacerbation reduced from 3.1 to 1.4 episodes/year (p=0.006) in the 12 months after treatment initiation compared with the 12 months before. A significant reduction in the frequency of hospital admissions/year was also observed (0.8 to 0.3, p=0.04). These findings support further prospective studies

Aberrant Disgust Responses and Immune Reactivity in Cocaine-Dependent Men

Background: Infectious diseases are the most common and cost-intensive health complications associated with drug addiction. There is wide belief that drug-dependent individuals expose themselves more regularly to disease-related pathogens through risky behaviors such as sharing pipes and needles, thereby increasing their risk for contracting an infectious disease. However, evidence is emerging indicating that not only lifestyle but also the immunomodulatory effects of addictive drugs, such as cocaine, may account for their high infection risk. As feelings of disgust are thought to be an important psychological mechanism in avoiding the exposure to pathogens, we sought to investigate behavioral, physiological, and immune responses to disgust-evoking cues in both cocaine-dependent and healthy men. Methods: All participants (N = 61) were exposed to neutral and disgust-evoking photographs depicting food and nonfood images while response accuracy, latency, and skin conductivity were recorded. Saliva samples were collected before and after exposure to neutral and disgusting images, respectively. Attitudes toward disgust and hygiene behaviors were assessed using questionnaire measures. Results: Response times to disgust-evoking photographs were prolonged in all participants, and specifically in cocaine-dependent individuals. While viewing the disgusting images, cocaine-dependent individuals exhibited aberrant skin conductivity and increased the secretion of the salivary cytokine interleukin-6 relative to control participants. Conclusion: Our data provide evidence of a hypersensitivity to disgusting stimuli in cocaine-dependent individuals, possibly reflecting conditioned responses to noningestive sources of infection. Coupled with a lack of interoception of bodily signals, aberrant disgust responses might lead to increased infection susceptibility in affected individuals

Mucosal-Associated Invariant T (MAIT) cells are impaired in Th17 associated primary and secondary immunodeficiencies

The recently described Mucosal Associated Invariant T (MAIT) cells mediate specific recognition of bacterial and fungal vitamin B2 metabolites. As innate T cells, they possess broad effector responses, including IFN- including Iproduction, that are comparable to conventional T cell responses. Immunodeficiencies associated with systemic Th17 deficiency may also be compounded by defects in MAIT immunity. We evaluated Th17 immunity in this innate T cell compartment in primary (AD-HIES) and secondary immunodeficiency (thymoma) patients with conventional Th17 deficiency and susceptibility to fungal and bacterial disease. Our results suggest that MAIT cells are both reduced and functional deficient in STAT3 deficiency and thymoma patients with IL-12/23 autoantibodies. In contrast, thymoma patients without autoantibodies preserved the normal number and functional MAIT cells

Age-associated B cells predict impaired humoral immunity after COVID-19 vaccination in patients receiving immune checkpoint blockade

Age-associated B cells (ABC) accumulate with age and in individuals with different immunological disorders, including cancer patients treated with immune checkpoint blockade and those with inborn errors of immunity. Here, we investigate whether ABCs from different conditions are similar and how they impact the longitudinal level of the COVID-19 vaccine response. Single-cell RNA sequencing indicates that ABCs with distinct aetiologies have common transcriptional profiles and can be categorised according to their expression of immune genes, such as the autoimmune regulator (AIRE). Furthermore, higher baseline ABC frequency correlates with decreased levels of antigen-specific memory B cells and reduced neutralising capacity against SARS-CoV-2. ABCs express high levels of the inhibitory FcγRIIB receptor and are distinctive in their ability to bind immune complexes, which could contribute to diminish vaccine responses either directly, or indirectly via enhanced clearance of immune complexed-antigen. Expansion of ABCs may, therefore, serve as a biomarker identifying individuals at risk of suboptimal responses to vaccination

Anticytokine autoantibodies in infection and inflammation: an update

Purpose of review: Concise overview of the field of anticytokine autoantibodies with a focus on recent developments.Recent findings: Advances in particular in the analysis of autoantibodies to IFNγ, granulocyte-macrophage colony-stimulating factor (GM-CSF) and type I IFN are presented. The target epitope for anti-IFNγ autoantibodies has been found to have high homology to a protein from Aspergillus suggesting molecular mimicry as a mechanism of breaking self-tolerance. A treatment strategy using a recombinant, epitope-depleted version of IFNγ is suggested. Autoantibodies to GM-CSF are associated with disseminated Crytococcus and Nocardia infections thus expanding the spectrum of associated diseases beyond pulmonary alveolar proteinosis. Detailed analysis of anti-GM-CSF autoantibody clones derived from pulmonary alveolar proteinosis patients show evidence of high somatic mutation suggesting T cell-dependent affinity maturation; full GM-CSF neutralization is achieved by synergistic binding of antibodies targeting various distinct noncross-reactive epitopes and leading to antigen sequestration and Fc-mediated clearance. Single mAbs in contrast may lead to higher GM-CSF bioavailability. Anti type I IFN-specific autoantibodies derived from autoimmune polyglandular syndrome type I patients are of extreme high affinity and negatively correlate with the incidence of type I diabetes and may be thus considered to be protective. Hypomorphic severe combined immune deficiency may be associated with complex anticytokine patterns and the emergence of anti type I IFN autoantibodies correlates with severe viral infection histories.Summary: Anticytokine autoantibodies may cause susceptibility to infections. In autoimmune/autoinflammatory conditions, anticytokine autoantibodies may be protective or promote disease.</p

Interferon gamma replacement as salvage therapy in chronic pulmonary aspergillosis: effects on frequency of acute exacerbation and all-cause hospital admission

Chronic pulmonary aspergillosis (CPA) is often poorly responsive to antifungal treatment; secondary infections increase morbidity/mortality, particularly in progressive cases. Interferon gamma (IFNγ) has been implicated in not only Aspergillus control but also bacterial clearance. Clinical notes of patients with CPA treated with IFNγ (2011–2018) were retrospectively hand-searched. In patients treated for >12 months (n=20), the frequency of acute exacerbation reduced from 3.1 to 1.4 episodes/year (p=0.006) in the 12 months after treatment initiation compared with the 12 months before. A significant reduction in the frequency of hospital admissions/year was also observed (0.8 to 0.3, p=0.04). These findings support further prospective studies

466. Immunogenicity of 2 nd, 3 rd, 4 th SARS-CoV-2 Vaccines in Renal Patient Populations

Background: Dialysis, renal transplant (RTX) and autoimmune kidney disease (AKD) patients are at higher risk of COVD-19 and suboptimal humoral responses post primary SARS-CoV-2 vaccination. As such, these groups have been prioritised for further SARS-CoV-2 vaccine doses. Limited data are available on their immunogenicity. Methods: Patients on dialysis or with a RTX or AKD who received primary SARS-CoV-2 vaccination were prospectively recruited from three UK sites. SARS-CoV-2 IgG spike antibody (anti-S IgG) and nucleocapsid titres were measured with a Luminex assay post 2nd, 3rd and 4th SARS-CoV-2 vaccines. Endpoints were median anti-S IgG titres and seroconversion (anti-S IgG titre >1896 MFI). Results: 628 patients (58% male, median age 62 years) comprising 240 dialysis, 194 RTX, and 194 AKD patients were recruited, with seroconversion of 96%, 61% and 70% respectively post two vaccines, and median anti-S IgG titres (IQR) of 30604 (24393–31826), 5829 (455–28296) and 18711 (1233–30226). 400/627 (64%) had anti-S IgG titres post 3rd dose (82% BNT162b2, 7% mRNA-1273, 3% ChAdOx1, 8% unknown; median 191 days post 2nd dose), with 27/58 (47%) of RTX and 17/46 (37%) of AKD patient non-responders seroconverting. Seroconversion among RTX and AKD patients overall improved to 78% (114/146) and 79% (122/155) respectively (p< 0.05), but not in dialysis patients post 3rd dose. 212/400 (53%) had serology post 4th dose (66% BNT162b2, 22% mRNA-1273, 12% unknown; median 104 days post 3rd dose), with 10/22 (46%) and 3/25 (12%) of RTX and AKD patient non-responders seroconverting. Anti-S IgG titre and seroconversion were similar within each group post 4th dose (Table 1, Figure 1). Predictors of non-seroconversion post 3rd dose in a multivariable model were rituximab use within six months, mycophenolate, prednisolone, chronic kidney disease and AKD (all p< 0.05), and post 4th dose, rituximab alone (p< 0.001). Conclusion: After primary SARS-CoV-2 vaccination, a 3rd but not 4th dose improved anti-S IgG titres and seroconversion in renal patients. Immunosuppressive use, particularly rituximab, was associated with reduced serologic responses (Tables 2, 3). Patients on immunosuppressives should therefore be prioritised for consideration of additional pre-exposure prophylactic agents. Disclosures: Michael Chen-Xu, MBChB, MRCP, MPH, GSK: Grant/Research Support Rachel Jones, MD, GSK: Advisor/Consultant|GSK: Grant/Research Support|Roche: Grant/Research Support|Vifor Pharma: Advisor/Consultant Rona M. Smith, MD MRCP, GSK: Grant/Research Support|Union Therapeutics: Grant/Research Suppor

Simultaneous disseminated infections with intracellular pathogens: an intriguing case report of adult-onset immunodeficiency with anti-interferon-gamma autoantibodies

Background!#!Severe and disseminated non-tuberculous mycobacterial (NTM) infections are frequently linked to a genetic predisposition but acquired defects of the interferon gamma (IFNγ) / interleukin 12 (IL-12) pathway need to be considered in adult patients with persistent or recurrent infections. Neutralizing anti-IFNγ autoantibodies disrupting IFNγ signalling have been identified as the cause of a severe and unique acquired immunodeficiency syndrome with increased susceptibility to NTM and other intracellular pathogens.!##!Case presentation!#!An adult Asian female with a previous history of recurrent NTM infections presented with persistent diarrhea, abdominal pain, night sweats and weight loss. Severe colitis due to a simultaneous infection with cytomegalovirus (CMV) and Salmonella typhimurium was diagnosed, with both pathogens also detectable in blood samples. Imaging studies further revealed thoracic as well as abdominal lymphadenopathy and a disseminated Mycobacterium intracellulare infection was diagnosed after a lymph node biopsy. Further diagnostics revealed the presence of high-titer neutralizing anti-IFNγ autoantibodies, allowing for the diagnosis of adult-onset immunodeficiency with anti-IFNγ autoantibodies (AIIA).!##!Conclusions!#!We here present a severe case of acquired immunodeficiency with anti-IFNγ autoantibodies with simultaneous, disseminated infections with both viral and microbial pathogens. The case illustrates how the diagnosis can cause considerable difficulties and is often delayed due to unusual presentations. Histological studies in our patient give further insight into the pathophysiological significance of impaired IFNγ signalling. B-cell-depleting therapy with rituximab offers a targeted treatment approach in AIIA

Differential Impairment of Interferon-γ Responses in Two Cases of Pulmonary Nontuberculous Mycobacterial Disease

Nontuberculous mycobacteria (NTMs) are weakly virulent intracellular pathogens that are common in food and water supplies. The persistent culture of these organisms in the setting of clinical infection warrants investigation of immune function. In cases of isolated pulmonary NTM (PNTM) disease, underlying immune defects have not been clearly identified. We present two patients with isolated PNTM infection who demonstrated differentially impaired IFN-γ production across a range of stimuli. These cases show that cellular IFN-γ responses may be defective in a proportion of patient suffering PNTM disease and that when assessing responses, the stimulant used in the testing is important to delineate defective cell populations. Impaired IFN-γ responses to IL-12 + BCG seem to be a poor prognostic indicator in PNTM disease and in these cases were not improved by adjuvant IFN-γ