Ontogeny of the ferret humoral immune response.

Infant ferrets are born with nearly undetectable immunoglobulin levels, but by 9 days of age the infant ferret serum contains 77, 29, and 13% of adult mean serum levels of IgG, IgA, and IgM. Transmucosal uptake of IgG by the infant ferret occurred for the first 30 days of life. The specific anti-respiratory syncytial virus neutralizing titer of whole milk was 5.5 times higher than maternal serum despite a lower concentration of immunoglobulins in the milk.     

Tetraspanins in the humoral immune response

The tetraspanins represent a large superfamily of four-transmembrane proteins that are expressed on all nucleated cells. Tetraspanins play a prominent role in the organization of the plasma membrane by co-ordinating the spatial localization of transmembrane proteins and signalling molecules into 'tetraspanin microdomains'. In immune cells, tetraspanins interact with key leucocyte receptors [including MHC molecules, integrins, CD4/CD8 and the BCR (B-cell receptor) complex] and as such can modulate leucocyte receptor activation and downstream signalling pathways. There is now ample evidence that tetraspanins on B-lymphocytes are important in controlling antibody production. The tetraspanin CD81 interacts with the BCR complex and is critical for CD19 expression and IgG production, whereas the tetraspanin CD37 inhibits IgA production and is important for IgG production. By contrast, the tetraspanins CD9, Tssc6 and CD151 appear dispensable for humoral immune responses. Thus individual tetraspanin family members have specific functions in B-cell biology, which is evidenced by recent studies in tetraspanin-deficient mice and humans. The present review focuses on tetraspanins expressed by B-lymphocytes and discusses novel insights into the function of tetraspanins in the humoral immune response.     

Respiratory virus infection of mice provokes a permanent humoral immune response.

We have observed that respiratory virus infection of mice provokes an extremely persistent humoral immune reaction, due to a long-sustained population of antibody-secreting cells in the bone marrow. Theories of humoral immunity that strongly distinguish primary and secondary reactions thus may not adequately describe the immune response to respiratory viruses.     

Assessment of the humoral immune response to cancer

One of the deadly hallmarks of cancer is its ability to prosper within the constraints of the host immune system. Recent advances in immunoproteomics and high-throughput technologies have lead to profiling of the antibody repertoire in cancer patients. This in turn has lead to the identification of tumour associated antigens/autoantibodies. Autoantibodies are extremely attractive and promising biomarker entities, however there has been relatively little discussion on how to interpret the humoral immune response. It may be that autoantibody profiles hold the key to ultimately uncovering neoplastic associated pathways and through the process of immunosculpting the tumour may have yielded an immune response in the early stages of malignant tumour development. The aim of this review is to discuss the utility of the autoantibody response that is elicited as a result of malignancy and discuss the advantages and limitations of autoantibody profiling. This article is part of a Special Issue entitled: Translational Proteomics.     

Maturation of the humoral immune response as an optimization problem.

Efficient immune response often depends on the production of high affinity antibodies. We show analytically that the optimal strategy for a fast production of high affinity antibodies is to utilize a step-function mutation rate, i.e. a minimal mutation rate in early stages of the immune response, followed by a discontinuous switch to the maximal possible rate when the proliferating population of B-cells exceeds a threshold value. Our results are in accordance with the biological observations concerning the time of onset of the hypermutation process, and with the mutation rate during the later stages of the primary immune response. Indeed the hypermutation process plays a crucial role in responding to a prevailing pathogen at each round of immune response, and not only for coping with future infections. Moreover, as the effect of hypermutations is shown to be crucially dependent on the number of proliferating B-cells, its onset is not expected to depend on an external signal, but rather to be related to the clone's age. This suggests that the onset is host species specific, rather than pathogen specific. Another implication of the present results is that activation of hypermutations before the B-cell population has reached the critical size may impede the efficiency of the response.     

Effects of a commercial malathion dip preparation on the cellular and humoral immune response of BALB/c mice

Because of the widespread use of malathion as a treatment for ectoparasitism, a study was undertaken to determine the effects of a malathion dip preparation on the BALB/c mouse immune system. Mice were treated with either 2% (recommended dosage) or 8% solutions of malathion or a water control. The cellular immune response was evaluated by in vitro exposure of lymphocytes to mitogens, and the humoral immune response was assessed by using an enzyme-linked immunosorbent assay (ELISA) to quantify antibody production against sheep red blood cells (SRBC). Responses to the mitogens and to the SRBC were not significantly different between 2% and 8% malathion treated and water treated mice. Results indicated that malathion did not affect these two aspects of the mouse immune system when used as a 2% or 8% dipping solution.     

Hepatitis delta antigen. Antigenic structure and humoral immune response

Hepatitis delta virus (HDV) is a small RNA virus that is dependent on helper functions provided by hepatitis B virus. The hepatitis delta Ag (HDAg) is the only protein known to be made from the viral genome, from an ORF with a coding capacity of 214 amino acids. The immunogenic epitopes of HDAg and the immune response to it were mapped by the use of synthetic peptides, antipeptide antibodies, and human mAb. Antipeptide sera covering approximately 60% of the linear sequence reacted with liver-derived HDAg. Antisera from HDV-infected humans, chimpanzees, and woodchucks reacted with from 2 to 13 of 15 peptides. The epitopes of two human anti-HD mAb were mapped to overlapping but distinct epitopes in the region around residues 106-123. Sera from infected humans, chimpanzees, and woodchucks were also tested by competition with the mAb. Use of the peptides and antipeptide sera defined one region in the sequence (residues 52-93) which is immunodominant in the immune response to HDAg. Reactivity of both peptides and antipeptide antibodies was very broad, covering most or all of the linear sequence. Competition assays also provided information on conformational epitopes, as well as the sequential epitopes defined by direct assays. The peptides and antipeptide antibodies should be useful in new assay development, in dissecting the anti-HD response in terms of chronic vs self-limited infection, and in studying the role of anti-HD in infection and recovery.     

Effects of bile acids on hepatocellular signaling and secretion.

Bile acids modulate hepatocellular signaling pathways in vitro at physiological concentrations. The present paper provides a brief overview of the effects of bile acids on three key messengers in liver cells: cytosolic free calcium, protein kinase A and protein kinase C.     

Immunosuppressive effect of cyclosporin A on insect humoral immune response

Cyclosporin A suppressed humoral immune response of Galleria mellonella larvae. Insects were immunized with LPS Pseudomonas aeruginosa and then injected with cyclosporin A. Immunosuppressive effects were expressed both, in larvae treated with cyclosporin A at the initial phase of immune response and at the effector phase of antibacterial immunity. Cyclosporin A moderately decreased lysozyme activity and significantly decreased antibacterial activity peptides against Escherichia coli. Immunosuppressive effects of cyclosporin A were observed after immunoblotting with antibodies anti-G. mellonella lysozyme. Tricine SDS/PAGE shown that synthesis of antibacterial peptides of larvae treated with cyclosporin A was considerably inhibited. Insects of impaired immune response by cyclosporin A action lost protective immunity to insect bacterial pathogen P. aeruginosa.     

The effect of synthetic protein fragments on humoral immune response

Effect of some protein and immunopeptide synthetic fragments on the humoral immune response has been studied. Some investigated peptides are shown to influence the antibody genesis at the secondary immune response to T-dependent antigen (bovine serum albumin) in mice. The serum antibody level specific for the bovine serum albumin is measured by enzyme-linked immunosorbent assays (ELISA). Possible mechanisms of the influence of such peptide fragments on the immune system is discussed.     

Dynamical analysis of a degenerate primary and secondary humoral immune response

Lymphocyte receptor response to antigen is degenerate. Each receptor can have a high affinity to more than one antigen. The optimal level of degeneracy was previously modeled using different methods; all showing that the degeneracy level should be inversely proportional to the probability that an antigen belongs to the self repertoire. Here we develop a new formalism, reproducing the results of previous models, which enables us to study the relation between receptor degeneracy and the pathogen-immune cell interaction dynamics, in primary and secondary response. We begin by developing a general formalismand reproducing the results obtained by Nemazee: (1) that an optimal immune system will have a capacity which is inversely proportional to the fraction of self-antigens and (2) that the number of self-reactive cells that the body destroys is tuned by this capacity optimization to be 63%. We then use our extended framework to relate the minimal number of B cell precursor required to mount an immune response to the naive B cell production rate. Finally, we analyze the dynamics of the interaction between the immune system and a pathogen and show that memory cells may be used as the first line of defense, while newly created cells are used later to refine the immune response.     

Combinations of two synthetic adjuvants: synergistic effects of a surfactant and a polyanion on the humoral immune response

Synergistic effects of two synthetic adjuvants, dimethyldioctadecylammonium bromide (DDA) and dextran sulfate (DXS) on the humoral response to sheep red blood cells (SRBC) were investigated. Mice received intraperitoneal (ip) injections of adjuvant and antigen simultaneously. The number of plaque-forming cells (PFC) in the spleen were determined 5 days later and circulating anti-SRBC antibodies were measured till 16 weeks after immunization. Although combinations of DDA and DXS were very effective in enhancing the PFC response to both moderate (2 X 10(7] and low (2 X 10(6] doses of SRBC, synergy between the adjuvants was only observed at the low dose of SRBC. Optimal augmentation of the primary response to the low antigen dose was evoked by the combination of the highest dose tested of either adjuvant (1 mumol DDA and 1 nmol DXS) resulting in a 560-fold increase of the number of PFC in the spleen as compared to controls. Even combinations of relatively small amounts of both adjuvants were very effective in augmenting the response to SRBC. Mice receiving half the amounts of both adjuvants with 2 X 10(6) SRBC displayed increased numbers of PFC in the spleen at Day 5 as well as increased titers of total anti-SRBC antibodies at Week 1 and Week 2 and 2-mercaptoethanol-resistant antibodies from Week 4 till Week 16 as compared to the calculated sum of responses in mice which received either DDA (0.05 mumol per mouse) or DXS (0.05 nmol per mouse). The mechanism behind the synergy between these adjuvants is discussed and the possibility of discerning adjuvants on their modes of action is suggested.     

Study of the phases of development of humoral immune response

In previously performed investigations to make clinical immunological diagnosis the principle of humoral immune response division into phases was put forward. The phases of humoral immune response were determined with lower content of immunoglobulins.     

Different effects of cortisone on the humoral immune response to T-dependent and T-independent antigens.

The effect of the administration of cortisone on the murine humoral immune response to either thymus-dependent (TD) or -independent (TI) antigens was studied in vivo. Whereas the thymus-dependent immune response was markedly suppressed, the thymus-independent immune response was preserved. The opposing effect of steroids on these two types of immune responses appears to be due to the relative independence of thymus-independent antigens of a radioresistant cortisone-sensitive accessory cell.     

A dynamic continuum model for molecular regulation of the humoral immune response.

Based on current concepts of the nature of specific immunocompetent cell surface receptors, hematopoietic stem cell differentiation and membrane dynamics, a simple model is proposed by which the event of immunogen binding by cell surface receptors specifically stimulates a constitutive process. The concept that enhancement of process flows in two directions with time allows for correlation of recent experimental findings into a molecular theory for antibody induction. The Model helps explain antibody specificity, heterogeneity and affinity changes and rationalizes immune memory.     

Role of the humoral immune response in resistance to Theiler''s virus infection.

Theiler's virus, a murine picornavirus, persists in the central nervous system of susceptible strains of mice, causing chronic inflammation and demyelination in the white matter of the spinal cord. Resistant strains, however, clear the virus and do not develop late disease. In this study, we compared the characteristics of T and B lymphocytes in C57BL/6 (resistant) and SJL/J (susceptible) mice 1 week after intracerebral infection. We detected a marked increase of the number of immunoglobulin M (IgM)-secreting cells in the spleens of C57BL/6 detected a marked increase of the number of immunoglobulin M (IgM)-secreting cells in the spleens of C57BL/6 mice (but not in those of SJL/J mice), which correlated with higher levels of serum IgM antiviral antibodies. The role of the humoral response in virus clearance and resistance was demonstrated by a marked decrease in the number of infected spinal cord cells in SJL/J mice after passive transfer of serum from infected C57BL/6 donors. The B-cell response was found to be partly T cell independent. These results suggest an important role of the early humoral immune response in resistance to Theiler's virus-induced disease.