Cellular and humoral immune responses to measles in immune adults re-immunized with measles vaccine

The objective of this study was to characterize the kinetics of the cellular and humoral immune responses elicited by measles vaccine given to previously immune adults. The cellular and humoral immune responses to measles were measured in seven healthy adults, before vaccination and at 1, 2, 3, and 4 weeks and 3 months after vaccination, using measles-specific T-cell proliferation and plaque reduction neutralization assays. All study subjects had detectable measles antibodies, but only six (85%) showed protective titers, defined as >1:120, before immunization. However measles-specific T-cell proliferation was not detectable before vaccination in any of the subjects. The six subjects with protective titers showed a positive stimulation index (SI) of >3.0 within the first 4 weeks after vaccination, an SI of 5 at the 4th week, and an SI of 3 at 3 months after vaccination. The subject with a low antibody titer (1:99) before vaccination developed a high SI at 3 months after vaccination. This subject was the only participant whose neutralizing antibody titers increased more than 4-fold by 3 months after vaccination. No significant increases in geometric mean titers were detected in the other six subjects during the follow-up period. These data suggest that high measles antibody titers interfere with the humoral response in subjects who receive a booster immunization, whereas the cellular response is boosted at least transiently, after revaccination.     

Innate immune responses in children and adults with Shigellosis

An array of pro- and anti-inflammatory mediators of the innate immune system was analyzed in stool, urine, and rectal mucosa samples from adults and children with shigellosis to better understand their role in recovery from and in the immunopathogenesis of the disease. Increased concentrations of lactoferrin (Lf), myeloperoxidase (MPO), prostaglandin E(2), and leukotriene B(4) (LTB(4)) in stool during acute shigellosis in both children and adults indicated that activated cells of the innate defense system at the mucosal site were secreting the mediators. Increased concentration of MPO and 8-iso-prostaglandin F(2alpha) and lower levels of superoxide dismutase (SOD) activity in stool during acute Shigella infection suggested increased formation of reactive oxygen species, free radical-catalyzed peroxidation of membrane lipids, and decreased scavenging of the reactive oxygen radicals. In children, lower expression of SOD in tissue with severe inflammation and lower levels of SOD activity in stool for longer periods compared to adults may further worsen the tissue damage and predispose the children to a lowered defense. Both adult and pediatric patients had significantly higher expression of inducible nitric oxide synthase (iNOS) in the rectum with severe inflammation, compared to that seen with mild inflammation, accompanied by persistently up-regulated iNOS mRNA, reflecting increased production of nitric oxide at the local site. However, in contrast to adults, reduced urinary nitrate levels in pediatric patients during acute shigellosis suggested lower production of nitric oxide in the renal compartment. Persistent production of Lf in pediatric patients may contribute to chronic inflammation in the rectum. In addition, increased production of proinflammatory mediators in the rectum of patients with severe histology suggested contribution of these molecules to the immunopathogenesis of severe colitis caused by shigellae.     

Peripheral blood neutrophil responses in children with shigellosis.

Alterations in peripheral blood neutrophil function are known to occur in patients with colitis and may have a role in precipitating nonspecific tissue injury. It is not known whether neutrophil function is altered in patients with Shigella dysenteriae type 1 infection, during which there is extensive colitis and which may be associated with life-threatening complications in young children. Three aspects of peripheral blood neutrophil function, polarization, attachment to yeast particles, and locomotion, were therefore studied in 111 children with S. dysenteriae type 1 infection and 57 children without any infection. All children were aged 12 to 60 months. Of the children with S. dysenteriae type 1 infection, 42 had leukemoid reaction, hemolytic-uremic syndrome, or septicemia (complicated shigellosis), while the others did not (uncomplicated shigellosis). Polarization and locomotion in the absence of chemoattractants and in response to N-formylmethionyl-leucylphenylalanine (FMLP) and the lipopolysaccharide (LPS) of S. dysenteriae type 1 were determined. Attachment to unopsonized and opsonized yeast particles was also determined. Children with shigellosis (uncomplicated or complicated) had more polarized neutrophils with and without chemoattractants than uninfected children (P < 0.05). Children with complicated shigellosis had more polarized neutrophils with FMLP at 10(-7) and 10(-6) M (P < 0.05) and with LPS than children with uncomplicated shigellosis (P < 0.05). At 3 to 5 days after enrollment, the numbers of polarized neutrophils with 10(-8), 10(-6), and 10(-5) M FMLP declined in children with uncomplicated shigellosis but not in those with complicated shigellosis. Attachment to yeast particles was similar in all three groups of children. Locomotion was inhibited by LPS in children with shigellosis (P < 0.05), whether it was uncomplicated or complicated, compared with locomotion in uninfected children. Finally, neutrophil polarization in uninfected children was negatively influenced by nutritional status. Thus, poorly nourished uninfected children had more polarized neutrophils with FMLP at 10(-9) M (P < = 0.02) and 10(-5) M (P = 0.043) than their better-nourished counterparts. In summary, altered neutrophil responses are associated with both uncomplicated and complicated shigellosis.     

Complement and the regulation of humoral immune responses

The complement component C3 is involved in the successful induction of a normal antibody response, but its mode of action is unclear. From studies with complement deficient guinea pigs Erik Böttger and Dieter-Suermann suggest that failure to stimulate antibody generation is the result of C3 depletion, rather than the suppression of activation by C3 fragments. In addition, they propose that complement may have a second regulatory function, being indirectly or directly involved in the suppression of the polyclonal activation of lymphocytes.     

Cell-mediated and humoral adaptive immune responses to SARS-CoV-2 are lower in asymptomatic than symptomatic COVID-19 patients

The characterization of cell-mediated and humoral adaptive immune responses to SARS-CoV-2 is fundamental to understand COVID-19 progression and the development of immunological memory to the virus. In this study, we detected T-cells reactive to SARS-CoV-2 proteins M, S, and N, as well as serum virus-specific IgM, IgA, IgG, in nearly all SARS-CoV-2 infected individuals, but not in healthy donors. Virus-reactive T cells exhibited signs of in vivo activation, as suggested by the surface expression of immune-checkpoint molecules PD1 and TIGIT. Of note, we detected antigen-specific adaptive immune response both in asymptomatic and symptomatic SARS-CoV-2 infected subjects. More importantly, symptomatic patients displayed a significantly higher magnitude of both cell-mediated and humoral adaptive immune response to the virus, as compared to asymptomatic individuals. These findings suggest that an uncontrolled adaptive immune response contribute to the development of the life-threatening inflammatory phase of the disease. Finally, this study might open the way to develop effective vaccination strategies.     

Cellular and humoral immune responses in Campylobacter pylori-associated chronic gastritis

Gastric cellular and humoral immune response investigated by immunoperoxidase staining of 53 antral biopsies showed significant differences in Campylobacter pylori-associated gastritis as compared with non-bacterial chronic gastritis and normal controls. IgA, secretory component, and complement C3 coated bacilli were seen in all cases of active chronic gastritis. C3 was always associated with coating by IgA, IgM, or both, which were rarely seen in gastritis without polymorphonuclear neutrophil infiltration. Intraepithelial mononuclear cellular infiltration was seen in 18 of 26 cases of C. pylori-associated chronic gastritis. The intraepithelial mononuclear cells stained positively for T cells and histiocytes.     

Equine neonates have attenuated humoral and cell-mediated immune responses to a killed adjuvanted vaccine compared to adult horses

The objectives of this study were to compare relative vaccine-specific serum immunoglobulin concentrations, vaccine-specific lymphoproliferative responses, and cytokine profiles of proliferating lymphocytes between 3-day-old foals, 3-month-old foals, and adult horses after vaccination with a killed adjuvanted vaccine. Horses were vaccinated intramuscularly twice at 3-week intervals with a vaccine containing antigens from bovine viral respiratory pathogens to avoid interference from maternal antibody. Both groups of foals and adult horses responded to the vaccine with a significant increase in vaccine-specific IgGa and IgG(T) concentrations. In contrast, only adult horses and 3-month-old foals mounted significant vaccine-specific total IgG, IgGb, and IgM responses. Vaccine-specific concentrations of IgM and IgG(T) were significantly different between all groups, with the highest concentrations occurring in adult horses, followed by 3-month-old foals and, finally, 3-day-old foals. Only the adult horses mounted significant vaccine-specific lymphoproliferative responses. Baseline gamma interferon (IFN-γ) and interleukin-4 (IL-4) concentrations were significantly lower in 3-day-old foals than in adult horses. Vaccination resulted in a significant decrease in IFN-γ concentrations in adult horses and a significant decrease in IL-4 concentrations in 3-day-old foals. After vaccination, the ratio of IFN-γ/IL-4 in both groups of foals was significantly higher than that in adult horses. The results of this study indicate that the humoral and lymphoproliferative immune responses to this killed adjuvanted vaccine are modest in newborn foals. Although immune responses improve with age, 3-month-old foals do not respond with the same magnitude as adult horses.     

Co-evolution of parasites and adaptive immune responses

The interplay between evolving host populations and evolving parasite populations is dominated by two key genetically based elements, namely the virulence of parasites and the resistance of their hosts. Here, Graham Mitchell gives a personal overview of ideas on the coevolution of parasite-host relationships and the contributions to immunology that are likely to emerge from systematic studies on this relationship.     

Nature of immune lymph node factors stimulating humoral and cellular immune responses

Institute of Immunology, Ministry of Health of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR A. D. Ado.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 107, No. 4, pp. 460–462, April, 1989.     

Linear ubiquitination signals in adaptive immune responses

Ubiquitin can form eight different linkage types of chains using the intrinsic Met 1 residue or one of the seven intrinsic Lys residues. Each linkage type of ubiquitin chain has a distinct three-dimensional topology, functioning as a tag to attract specific signaling molecules, which are so-called ubiquitin readers, and regulates various biological functions. Ubiquitin chains linked via Met 1 in a head-to-tail manner are called linear ubiquitin chains. Linear ubiquitination plays an important role in the regulation of cellular signaling, including the best-characterized tumor necrosis factor (TNF)-induced canonical nuclear factor-κB (NF-κB) pathway. Linear ubiquitin chains are specifically generated by an E3 ligase complex called the linear ubiquitin chain assembly complex (LUBAC) and hydrolyzed by a deubiquitinase (DUB) called ovarian tumor (OTU) DUB with linear linkage specificity (OTULIN). LUBAC linearly ubiquitinates critical molecules in the TNF pathway, such as NEMO and RIPK1. The linear ubiquitin chains are then recognized by the ubiquitin readers, including NEMO, which control the TNF pathway. Accumulating evidence indicates an importance of the LUBAC complex in the regulation of apoptosis, development, and inflammation in mice. In this article, I focus on the role of linear ubiquitin chains in adaptive immune responses with an emphasis on the TNF-induced signaling pathways.     

Cell-mediated and humoral immune responses of renal transplant recipients with cytomegalovirus infections

Cell-mediated and humoral immune responses were determined in immunosuppressed renal transplant recipients. A micro-phytohaemagglutinin (PHA) stimulation test utilizing whole heparinized blood and a macro-PHA test utilizing separated, washed lymphocytes were used to study cell-mediated immunity. Humoral immune status was estimated by determining quantitative immunoglobulins and complement fixing (CF) antibody titres to cytomegalovirus (CMV) infection. Micro-PHA responses were found to be markedly depressed in patients undergoing immunosuppressive therapy and in patients with chronic uraemia. Macro-PHA responses were normal, indicating that serum factors were responsible for the depressed micro-PHA responses. Antibody responses to CMV infections were found to be ten to a hundred times higher than in normal persons. An inverse relationship was demonstrated between micro-PHA responses and peak CF antibody titres to CMV infections. Humoral immune responses appeared to compensate for depressed cell-mediated immunity as measured by the micro-PHA test. Four patients had very low micro-PHA responses, did not respond to their CMV infections with CF antibody, and died of mixed bacterial and viral infections. Serum immunoglobulins of two were studied and were shown to be greater than two standard deviations below the normal mean. These patients appeared more suppressed than other patients receiving similar therapy and thus probably retained higher concentrations of suppressive drugs.     

Modulation of humoral immune responses by endogenous opioids

The effects of opioid agonists and antagonists were investigated on humoral immune mechanisms in mice and rats. Opioid agonists like morphine, Leu-enkephalin, and Met-enkephalin, enhanced antigen-induced histamine release from mixed peritoneal cells of rats in vitro; this enhancement was effectively antagonized by naloxone, an opioid antagonist. Naloxone, per se, decreased anaphylactic mortality in doses of 10 mg/kg, while it increased mortality in a dose of 1 mg/kg. Reduced IgE antibody titer, measured by passive cutaneous anaphylaxis, decreased hemagglutination titer to sheep red blood cells, blocked histamine release from mixed peritoneal cells of rats in vitro induced by antigen, but had no significant effect when histamine release was induced by compound 48/80. Thus, it appears that endogenous opioids are involved in humoral immune responses.     

Innate and adaptive immune responses in neurodegeneration and repair

Emerging evidence suggests important roles of the innate and adaptive immune responses in the central nervous system (CNS) in neurodegenerative diseases. In this special review issue, five leading researchers discuss the evidence for the beneficial as well as the detrimental impact of the immune system in the CNS in disorders including Alzheimer''s disease, multiple sclerosis and CNS injury. Several common pathological mechanisms emerge indicating that these pathways could provide important targets for manipulating the immune reposes in neurodegenerative disorders. The articles highlight the role of the traditional resident immune cell of the CNS - the microglia - as well as the role of other glia astrocytes and oligodendrocytes in immune responses and their interplay with other immune cells including, mast cells, T cells and B cells. Future research should lead to new discoveries which highlight targets for therapeutic interventions which may be applicable to a range of neurodegenerative diseases.     

Adhesive substrate-modulation of adaptive immune responses

While it is well-known that adsorbed proteins on implanted biomaterials modulate inflammatory responses, modulation of dendritic cells (DCs) via adhesion-dependent signaling has only been begun to be characterized. In this work, we demonstrate that adhesive substrates elicit differential DC maturation and adaptive immune responses. We find that adhesive substrates support similar levels of DC adhesion and expression of stimulatory and co-stimulatory molecules. Conversely, DC morphology and differential production of pro- and anti-inflammatory cytokines (IL-12p40 and IL-10, respectively) is adhesive substrate-dependent. For example, DCs cultured on collagen and vitronectin substrates generate higher levels of IL-12p40, whereas DCs cultured on albumin and serum-coated tissue culture-treated substrates produce the higher levels of IL-10 compared to other substrates. Additionally, our results suggest substrate-dependent trends in DC-mediated allogeneic CD4(+) T-cell proliferation and T-helper cell type responses. Specifically, we show that substrate-dependent modulation of DC IL-12p40 cytokine production correlates with CD4(+) T-cell proliferation and T(h)1 type response in terms of IFN-gamma producing T-helper cells. Furthermore, our results suggest substrate-dependent trends in DC-mediated stimulation of IL-4 producing T-cells, but this T(h)2 type response is not dependent on DC production of IL-10 cytokine. This work has impact in the rational design of biomaterials for diverse applications such as tissue-engineered constructs, synthetic particle-based vaccines and the ex vivo culture of DCs for immunotherapies.     

Interrelations of humoral and cellular immune responses in experimental canine gastritis

Experimental canine gastritis is an animal model with features similar to the gastritis of human pernicious anaemia. In this study eight mongrel dogs immunized with autologous or homologous gastric juice in Freund' scomplete adjuvant developed gastritis whereas four mongrel dogs immunized with the adjuvant alone did not. Cellular immunity to gastric juice antigens demonstrated by skin testing and peripheral leucocyte migration inhibition coincided with the appearance of gastritis, whereas parietal cell antibodies appeared some 2 weeks later. The work demonstrates the combined humoral and cellular immune response of the dogs to gastric juice, and suggests that the cellular response may be of primary importance in the development of gastritis.     

IL-2 infusion abrogates humoral immune responses in humans.

Although IL-2 infusion enhances cell-mediated cytotoxicity in patients with neoplastic disease, administration is paradoxically associated with a modest fall in total serum IgG and an increased risk of infection. We now show that the adverse effects of IL-2 infusion on the humoral immune system are substantial. Although IL-2 induces the B cell growth and differentiating factors IL-4 and IL-6, infusion abrogates primary antibody responses entirely and reduces secondary antibody responses 50-fold following antigen challenge. There is no evidence of the generation of cells with suppressive activity on B cells but IL-2 increases the ratio of circulating virgin:memory cells. These results may help to explain the increased rate of bacterial infection in patients receiving IL-2. As IL-2 plays a central role in the generation of an immune response, the finding that it is also sufficiently immunosuppressive to inhibit primary- and secondary-type antibody responses suggests that exploration of the underlying mechanisms may provide insights into immune system homeostasis and may offer new approaches to therapeutic immunosuppression.     

DAMPs activating innate and adaptive immune responses in COPD

Chronic obstructive pulmonary disease (COPD), a progressive lung disease characterized by sustained neutrophilic airway inflammation, is caused by chronic exposure to noxious stimuli, e.g., cigarette smoke. This chronic exposure can induce immunogenic cell death of structural airway cells, inducing the release of damage-associated molecular patterns (DAMPs). Levels of several DAMPs, including S100 proteins, defensins, and high-mobility group box-1 (HMGB1), are increased in extracellular lung fluids of COPD patients. As DAMPs can attract and activate immune cells upon binding to pattern recognition receptors, we propose that their release may contribute to neutrophilic airway inflammation. In this review, we discuss the novel role of DAMPs in COPD pathogenesis. Relevant DAMPs are categorized based on their subcellular origin, i.e. cytoplasm, endoplasmic reticulum, nucleus, and mitochondria. Furthermore, their potential role in the pathophysiology of COPD will be discussed.