The probability of contact between the immunocompetent cell and antigen

The present work is an attempt to make a mathematical formulation of the first part of a well-known hypothesis (Šterzl, 1967) dealing with the course of differentiation of an immunocompetent cell into an antibody-producing cell, namely with the early event—the contact between the cell and antigen. The probability of an event, namely that during the given time interval the contact between the immunocompetent cell and antigen will take place, was studied. The corresponding probability distribution depends substantially on the function describing the fate of antigen following its injection into the organism and further, on the amount of active antigen that is present in the organism in dependence on the length of time after the antigen injection. In addition to a general formula, formula were even obtained describing one particular important function of the decrease in the amount of antigen (exponential).     

On contacts of immunocompetent cells with antigen (Note on a probability model)

This communication continues with the mathematical formulation and solution of some problems connected with the beginning of the immunological reaction. This paper generalizes some previous results concerning the probability of the event that such a contact of an immunocompetent cell (ICC) with antigen, which is followed by the differentiation of this cell towards the antibody forming cell (AbFC), takes place. Previous papers considered the onset of the differentiation of an ICC caused by the contact of this cell with at least a certain threshold amount of antigen (assuming that these contacts form a non-homogeneous Poisson process). This paper is based on the more general and more realistic assumption thatn such contacts are necessary for the stimulation of ICC differentiation (this new assumption has its origin in some new biological findings on the nature of the contact considered, and corresponds with the idea that the diffentiation of ICC does not begin until the antigen is bound on a certain fixed number of receptors on the cell surface). Under this assumption, the probability of the event that the differentiation of the cell begin at all (i.e. that at leastn contacts will take place), and the probability distribution of the epoch of the beginning of the differentiation (i.e. of the epoch at which thenth contact take place), are derived.— If necessary, these new forms of probability distributions may be used (instead of previous ones) as building stones in models of ICC differentiation.     

Reduced immunocompetence of nestlings in replacement clutches of the European magpie (Pica pica)

Laying date is one of the most important determinants of reproductive success and recruitment probability in birds. Late breeders usually fledge fewer chicks than individuals with earlier breeding dates, and fledglings produced late in the season have high mortality rates. Food availability and nestling mass have been evoked as the principal mechanistic links between laying date and offspring survival. Here we suggest that another factor may actually account for the difference in survival rate between early and late offspring: immunocompetence. We predicted that nestlings produced later in the season or in replacement clutches should have lower immune responses when challenged with an antigen, than early nestlings or nestlings produced in first clutches. This hypothesis was tested in a population of magpies (Pica pica), in which we experimentally induced breeding failure in a group of nests and compared the immune response of nestlings in replacement clutches with the immune response of first clutch nestlings. Cellular immune response, as measured by wing web swelling (a correlate of T-lymphocyte production after injection of phytohaemagglutinin-P), significantly decreased with hatching date and was significantly lower in nestlings of replacement clutches. Furthermore, coefficients of intraclutch variation in immune response were higher in nestlings of replacement clutches. This experiment demonstrates an inverse relationship between immune responsiveness and breeding date, and reduced recruitment probability of late nestlings may be a direct consequence of their inability to cope with parasites.     

Reprint of Hormonal correlates of pathogen disgust: testing the compensatory prophylaxis hypothesis

Raised progesterone during the menstrual cycle is associated with suppressed physiological immune responses, reducing the probability that the immune system will compromise the blastocyst's development. The Compensatory Prophylaxis Hypothesis proposes that this progesterone-linked immunosuppression triggers increased disgust responses to pathogen cues, compensating for the reduction in physiological immune responses by minimizing contact with pathogens. Although a popular and influential hypothesis, there is no direct, within-woman evidence for correlated changes in progesterone and pathogen disgust. To address this issue, we used a longitudinal design to test for correlated changes in salivary progesterone and pathogen disgust (measured using the pathogen disgust subscale of the Three Domain Disgust Scale) in a large sample of women (N?=?375). Our analyses showed no evidence that pathogen disgust tracked changes in progesterone, estradiol, testosterone, or cortisol. Thus, our results provide no support for the Compensatory Prophylaxis Hypothesis of variation in pathogen disgust.     

Hormonal correlates of pathogen disgust: testing the compensatory prophylaxis hypothesis

Raised progesterone during the menstrual cycle is associated with suppressed physiological immune responses, reducing the probability that the immune system will compromise the blastocyst's development. The Compensatory Prophylaxis Hypothesis proposes that this progesterone-linked immunosuppression triggers increased disgust responses to pathogen cues, compensating for the reduction in physiological immune responses by minimizing contact with pathogens. Although a popular and influential hypothesis, there is no direct, within-woman evidence for correlated changes in progesterone and pathogen disgust. To address this issue, we used a longitudinal design to test for correlated changes in salivary progesterone and pathogen disgust (measured using the pathogen disgust subscale of the Three Domain Disgust Scale) in a large sample of women (N = 375). Our analyses showed no evidence that pathogen disgust tracked changes in progesterone, estradiol, testosterone, or cortisol. Thus, our results provide no support for the Compensatory Prophylaxis Hypothesis of variation in pathogen disgust.     

Liposome-Mediated Cytoplasmic Delivery of Proteins: An Effective Means of Accessing the MHC Class I-Restricted Antigen Presentation Pathway

Different types of liposomes have been employed to deliver soluble antigen for processing and presentation in the major histocompatibility complex class I-restricted pathway. Anionic pH-sensitive liposomes as well as cationic liposomes efficiently sensitize antigen-presenting cells for recognition by the class I-restricted cytotoxic T lymphocytes (CTL). Cytoplasmic delivery of liposome-entrapped antigen from an endocytic compartment allows the exogenous antigen to gain access to the class I presentation pathway. Cytoplasmic delivery, however, is probably not the only mechanism by which liposomes induce the class I-restricted CTL priming in vivo. Macrophages play a central role in the processing of the liposome-encapsulated antigens. The processed antigen fragments are probably released by the macrophages and taken up by the nearby dendritic cells for antigen presentation. Collaboration between the two types of immune cells with the help of the appropriate costimulatory factors is the central theme for this hypothesis. In this case, the host immune system utilizes the similar mechanism for other membranous, particulate antigens to process and present the liposomal antigens.     

CTLA-4 blockade and the renaissance of cancer immunotherapy

Cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) plays a key role in restraining the adaptive immune response of T-cells towards a variety of antigens including tumor associated antigens (TAAs). The blockade of this immune checkpoint elicits an effective anticancer immune response in a range of preclinical models, suggesting that naturally occurring (or therapeutically induced) TAA specific lymphocytes need to be “unleashed” in order to properly fight against malignant cells. Therefore, investigators have tested this therapeutic hypothesis also in humans: the favorable results obtained with this strategy in patients with advanced cutaneous melanoma are revolutionizing the management of this highly aggressive disease and are fueling new enthusiasm on cancer immunotherapy in general.     

Simple sugars with affinity for the macrophage asialoglycoprotein receptor are adjuvants for the humoral immune response to neuraminidase-treated sheep erythrocytes

The influence of monosaccharides on the humoral immune response of mice to normal and neuraminidase-treated sheep red blood cells (SRBC) was investigated. In these studies, both the sugars and antigen were administered i.p. D-Galactose displayed adjuvant activity for neuraminidase-treated but not for normal SRBC. This activity was optimal at an antigen dose of 3 X 10(6) cells. Other monosaccharides with an axial hydroxyl group at position 4 and D-mannose-6-phosphate behaved like D-galactose, whereas structurally unrelated sugars did not. The adjuvant activity of the saccharides corresponded to the affinity of the substances for the asialo-glycoprotein receptor. The adjuvant effects were also expressed in cobra venom factor-treated and C5-deficient mice. This suggests that blockade of the asialo-receptor rather than complement is involved in this form of immunoadjuvant activity. The findings are also in support of our hypothesis that obstruction of nonimmune antigen elimination, in this case at the level of macrophages, would be one of the mechanisms underlying immunologic adjuvant activity.     

Influence of the fibroblastic reticular network on cell-cell interactions in lymphoid organs

Secondary lymphoid organs (SLO), such as lymph nodes and the spleen, display a complex micro-architecture. In the T cell zone the micro-architecture is provided by a network of fibroblastic reticular cells (FRC) and their filaments. The FRC network is thought to enhance the interaction between immune cells and their cognate antigen. However, the effect of the FRC network on cell interaction cannot be quantified to date because of limitations in immunological methodology. We use computational models to study the influence of different densities of FRC networks on the probability that two cells meet. We developed a 3D cellular automaton model to simulate cell movements and interactions along the FRC network inside lymphatic tissue. We show that the FRC network density has only a small effect on the probability of a cell to come into contact with a static or motile target. However, damage caused by a disruption of the FRC network is greatest at FRC densities corresponding to densities observed in the spleen of naïve mice. Our analysis suggests that the FRC network as a guiding structure for moving T cells has only a minor effect on the probability to find a corresponding dendritic cell. We propose alternative hypotheses by which the FRC network might influence the functionality of immune responses in a more significant way.     

Antigen-specific T contrasuppressor factor in cell-mediated immunity: interactions leading to eradication of the tolerant state

Interactions between a T cell-derived, antigen-specific, contrasuppressor factor (TcsF) and immune T cells that block the action of T suppressor factors and allow the transfer of cellular immunity into tolerant recipients are described. Immune T cells from contact-sensitized donors are capable of transferring specific immunity into normal recipients but not into animals rendered tolerant to the specific antigen. Brief exposure of the immune cells to the TcsF enables the effective transfer of immunity into such tolerant recipients. In addition, treated immune cells become resistant to subsequent exposure to T suppressor factor (capable of inhibiting transfer of immunity to normal recipients). A cyclophosphamide-sensitive, I-J+, Ly-2 T transducer cell is required in the immune donor cell population for contrasuppression to be induced by the TcsF plus specific antigen. These cells release an antigen-non-specific contrasuppressive factor capable of rendering immune targets, depleted of transducer cells, resistant to suppression (either by suppressor factor or in the tolerant recipient). The results indicate that contrasuppression in contact sensitivity is antigen specific and that the balance of suppression and contrasuppression determines tolerance vs responsiveness in this system. The symmetrical resemblance of the contrasuppressive interactions to those of suppression in contact sensitivity are discussed.     

A multi-scale model for correlation in B cell VDJ usage of zebrafish

The zebrafish (Danio rerio) is one of the model animals used for the study of immunology because the dynamics in the adaptive immune system of zebrafish are similar to that in higher animals. In this work, we built a multi-scale model to simulate the dynamics of B cells in the primary and secondary immune responses of zebrafish. We use this model to explain the reported correlation between VDJ usage of B cell repertoires in individual zebrafish. We use a delay ordinary differential equation (ODE) system to model the immune responses in the 6-month lifespan of a zebrafish. This mean field theory gives the number of high-affinity B cells as a function of time during an infection. The sequences of those B cells are then taken from a distribution calculated by a 'microscopic' random energy model. This generalized NK model shows that mature B cells specific to one antigen largely possess a single VDJ recombination. The model allows first-principle calculation of the probability, p, that two zebrafish responding to the same antigen will select the same VDJ recombination. This probability p increases with the B cell population size and the B cell selection intensity. The probability p decreases with the B cell hypermutation rate. The multi-scale model predicts correlations in the immune system of the zebrafish that are highly similar to that from experiment.     

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.     

Enhanced immune function does not depress reproductive output

Costs of reproduction might be mediated by a physiological (resource allocation) trade-off between immune function and reproductive effort, and several recent studies have shown that an experimental increase in reproductive effort is associated with decreased immune function. Here we test the complementary prediction of this hypothesis: that increased immune function (specific antibody production) depresses reproductive output. Female European starlings (Sturnus vulgaris) were injected with a non-pathogenic antigen (sheep red blood cells) following completion of laying of their first clutch, to stimulate an in vivo humoral immune response (primary antibody production). We induced laying of a second clutch by removing the first clutch, and assessed changes in reproductive performance in individual females pre- and post-treatment. Injection of sheep red blood cells produced a significant antibody response in 96% (n=29) of treated females, with titres comparable to previous studies (range 1 to 7). However, increased antibody production did not decrease primary or secondary female reproductive effort (re-laying interval, egg size, clutch size, chick growth or fledging success), compared with control, saline-injected birds (n=22). These data do not support a simple resource allocation model for the cost of reproduction, based on a reciprocal, negative relationship between resources allocated to immune function and reproduction.     

The use of chemiluminescence for assessing the physiological status of macrophages activated by pertussis preparations

The work deals with the comparative analysis of oxygen-dependent metabolic processes in the peritoneal macrophages of intact and immune, mice after their interaction with whole-cell pertussis vaccine (WCPV), dialyzed pertussis antigen (DPA) and fraction 2 of this antigen. The study revealed that WCPV, DPA and its fraction 2 modulated the production of active forms of oxygen by peritoneal macrophages, evaluated by means of luminol-dependent chemiluminescence (CL). The influence of WCPV of oxygen-dependent metabolic processes in macrophages after the first contacts with them had a dose-dependent character: low concentrations activated and higher concentrations suppressed the "respiratory" explosion. The immunization of animals abolished the effect of extinguishing CL on the contact of macrophages with high doses of WCPV and essentially increased the level of their CL response to all pertussis preparations in comparison with those for intact cells. DPA and its fraction 2 were not inferior to WCPV in their capacity for inducing the "respiratory" explosion, and in high doses they essentially surpassed WCPV doses in this capacity, especially on the first contact with macrophages.     

Stochastic competitive exclusion in the maintenance of the naïve T cell repertoire

Recognition of antigens by the adaptive immune system relies on a highly diverse T cell receptor repertoire. The mechanism that maintains this diversity is based on competition for survival stimuli; these stimuli depend upon weak recognition of self-antigens by the T cell antigen receptor. We study the dynamics of diversity maintenance as a stochastic competition process between a pair of T cell clonotypes that are similar in terms of the self-antigens they recognise. We formulate a bivariate continuous-time Markov process for the numbers of T cells belonging to the two clonotypes. We prove that the ultimate fate of both clonotypes is extinction and provide a bound on mean extinction times. We focus on the case where the two clonotypes exhibit negligible competition with other T cell clonotypes in the repertoire, since this case provides an upper bound on the mean extinction times. As the two clonotypes become more similar in terms of the self-antigens they recognise, one clonotype quickly becomes extinct in a process resembling classical competitive exclusion. We study the limiting probability distribution for the bivariate process, conditioned on non-extinction of both clonotypes. Finally, we derive deterministic equations for the number of cells belonging to each clonotype as well as a linear Fokker-Planck equation for the fluctuations about the deterministic stable steady state.     

What is an immunological synapse?

Immunological synapses (IS) are emerging as highly organized 3D structures -formed by surface and cytoplasmic signalling and cytoskeletal molecules – that assemble at the zone of contact between a T cell and an antigen presenting cell (APC). The IS control functions that allow APC and T cells modulate the immune response.     

EXCLUSION OF THE ROLE OF SECONDARY CONTACT IN AN ALLELE FREQUENCY CLINE IN THE MUSSEL MYTILUS EDULIS

We examined the hypothesis that secondary contact generates an allele-frequency cline at the aminopeptidase-I locus (Lap) in the marine mussel, Mytilus edulis. It has been proposed that variation at the Lap locus is neutral and that the cline results from secondary contact between differentiated oceanic and estuarine populations (Levinton, 1980). We tested this hypothesis by comparing the genotypic distributions in samples from the cline to distributions that incorporate mixing effects. We employed a statistical model that determines the degree of contact using a maximum likelihood estimator and then incorporates the mixing estimates into an expected distribution of genotypes. Wahlund effects resulting from possible admixture are thereby incorporated into the expected distribution. Failure of the model to reconcile the observed with the expected distribution of genotypes indicates that the observed population structure does not result from admixture. The null hypothesis of mixing was unable to explain about 33% of the samples. Combined tests demonstrated the general departure from the mixing model to be highly significant. The distribution of heterozygote discrepancies across the cline was inconsistent with the expectations of a mixing model. Therefore we reject explanations for the structure of the Lap cline that involve secondary contact. Selection directed at the Lap locus appears necessary to explain the genotypic structure of clinal populations.     

Non-equilibrium thermodynamics of marginal- and conditional-open chemical systems

Every open chemical system treated in this paper is restricted to the case involving a sequence of monomolecular reactions. Various kinds of probability distribution governing it are introduced according to the situations in which it is placed. The chemical system subject to marginal distribution is given the term marginal-open system MO. The open chemical system ō discussed by Nicolis and Babloyantz can be regarded as the limiting system of MO. For an open chemical system, itself in contact with an external reservoir of finite volume, the probability distribution conditioned on the marginal distribution for the external reservoir in an arbitrarily fixed state is more appropriate. Such an open chemical system is called a conditional-open system CO. However, in the case of the external reservoir of infinite volume, although it is not certainly trivial, another conditional probability distribution has to be proposed; it is derived on the hypothesis that the probability distribution for an arbitrary total number of molecules in the open chemical system is known. The open chemical system so specified is called conditional-open system $\text{C}\text{O}\text{?}$. It is shown that for each system $\text{MO, CO}\text{and}\text{C}\text{O}\text{?}$ the change of entropy starting from the steady state provides a Liapunov function under some conditions and that the steady state is asymptotically stable. The relation of the entropy change to non-equilibrium fluctuations of chemical components in each system is discussed in comparison with that in the corresponding open chemical system ō, for which the steady state surely exists and is always stable. It is shown that the concept of $\text{C}\text{O}\text{?}$ is useful for investigating the phenomenon of steady-state coupling.     

Parasite transmission modes and the evolution of virulence

A mathematical model is presented that explores the relationship between transmission patterns and the evolution of virulence for horizontally transmitted parasites when only a single parasite strain can infect each host. The model is constructed by decomposing parasite transmission into two processes, the rate of contact between hosts and the probability of transmission per contact. These transmission rate components, as well as the total parasite mortality rate, are allowed to vary over the course of an infection. A general evolutionarily stable condition is presented that partitions the effects of virulence on parasite fitness into three components: fecundity benefits, mortality costs, and morbidity costs. This extension of previous theory allows us to explore the evolutionary consequences of a variety of transmission patterns. I then focus attention on a special case in which the parasite density remains approximately constant during an infection, and I demonstrate two important ways in which transmission modes can affect virulence evolution: by imposing different morbidity costs on the parasite and by altering the scheduling of parasite reproduction during an infection. Both are illustrated with examples, including one that examines the hypothesis that vector-borne parasites should be more virulent than non-vector-borne parasites (Ewald 1994). The validity of this hypothesis depends upon the way in which these two effects interact, and it need not hold in general.     

The migration of lymphocytes into rat popliteal lymph nodes during antigenic promotion or competition between heterologous erythrocytes

The injection of chicken and sheep red blood cells (CRBC and SRBC) into rat popliteal lymph nodes either together or sequentially 2, 4, 6, or 8 days apart resulted in an enhanced immune response when the second antigen was injected 2 or 4 days after the injection of the first antigen (antigenic promotion) or a suppressed immune response when the second antigen was injected 6 days after the injection of the first antigen (antigenic competition). The immune response to either antigen was dependent upon the time of administration of the second antigen with respect to the first antigen. Lymphocyte migration into antigenically stimulated lymph nodes was greater when the two antigens were injected sequentially rather than together. Further, the migration of lymphocytes into the lymph node was enhanced when the second antigen was injected during the inductive or suppressive phase of the immune response to the first antigen (CRBC) regardless of whether the same (CRBC) or an antigenically unrelated antigen (SRBC) was used as the second antigen. While antigenic promotion may in part be explained by the increased rate at which lymphocytes migrate into lymph nodes, lymphocyte migration is also enhanced during antigenic competition. This suggests that while suppressor cells/factors may regulate the effector phase of an immune response they do not directly modulate the migration of blood-borne lymphocytes into the lymph node.