The roles for innate lymphoid cells in the human immune system.

From constituting a novel and obscure cell population, innate lymphoid cells (ILCs) are now accepted as a self-evident part of the immune system, contributing with unique and complementary functions to immunity by production of effector cytokines and interaction with other cell types. In this review, we discuss the redundant and complementary roles of the highly plastic human ILCs and their interaction with other immune cells with the ultimate aim of placing ILCs in a wider context within the human immune system.

Age-related changes in the metabolism and body composition of three dog breeds and their relationship to life expectancy.

We measured body composition and resting metabolic rates (RMR) of three dog breeds (Papillons, mean body mass 3.0 kg (n = 35), Labrador retrievers, mean body mass 29.8 kg (n = 35) and Great Danes, mean body mass 62.8 kg (n = 35)) that varied between 0.6 and 14.3 years of age. In Papillons, lean body mass (LBM) increased with age but fat mass (FBM) was constant; in Labradors, both LBM and FBM were constant with age, and in Great Danes, FBM increased with age but LBM was constant. FBM averaged 14.8% and 15.7% of body mass in Papillons and Labradors, respectively. Great Danes were leaner and averaged only 10.5% FBM. Pooling the data for all individuals, the RMR was significantly and positively associated with LBM and FBM and negatively associated with age. Once these factors had been taken into account there was still a significant breed effect on RMR, which was significantly lower in Labradors than in the other two breeds. Using the predictive multiple regression equation for RMR and the temporal trends in body composition, we modelled the expenditure of energy (at rest) over the first 8 years of life, and over the entire lifespan for each breed. Over the first 8 years of life the average expenditure of energy per kg LBM were 0.985, 0.675 and 0.662 GJ for Papillons, Labradors and Great Danes, respectively. This energy expenditure was almost 60% greater for the smallest compared with the largest breed. On average, however, the life expectancy for the smallest breed was a further 6 years (i.e. 14 years in total), whereas for the largest breed it was only another 6 months (i.e. 8.5 years in total). Total lifetime expenditure of energy at rest per kg LBM averaged 1.584, 0.918 and 0.691 GJ for Papillons, Labradors and Great Danes, respectively. In Labradors, total daily energy expenditure, measured by the doubly labelled water method in eight animals, was only 16% greater than the observed RMR. High energy expenditure in dogs appears positively linked to increased life expectancy, contrary to the finding across mammal species and within exotherms, yet resembling observations in other intra-specific studies. These contrasting correlations suggest that metabolism is affecting life expectancy in different ways at these different levels of enquiry.

Distinct VH repertoires in primary and secondary B cell lymphocyte subsets in the preimmune repertoire of A/J mice: the CRI-A idiotype is preferentially associated with the HSA(low) B cell subset.

The anti-arsonate immune response of A/J mice is characterized by the occurrence of several recurrent idiotypes with a different temporal pattern of expression. The CRI-A idiotype is typically a memory idiotype since it appears late in the primary and dominates the secondary as well as subsequent immune responses. The CRI-C idiotype is present throughout the responses, including the primary one. Naive adult A/J mice treated repeatedly with anti-mu or anti-delta monoclonal antibodies exhibit a completely different balance of HSA(low) and HSA(high) B cell subsets and an opposite idiotype profile after immunization with p-azophenylarsonate coupled to hemocyanin. Anti-mu treatment leads to a striking enhancement of the HSA(low) cell subset associated with an earlier important synthesis of CRI-A(+) antibodies, while anti-delta treatment enhances significantly the HSA(high) compartment with a strong decrease of CRI-A and persistence of CRI-C1 antibodies. Semiquantitative PCR analysis reveals that the presence of CRI-A transcripts is associated with the HSA(low) compartment, while CRI-C transcripts are mainly associated with HSA(high) B cell subsets. This has been demonstrated with spleen cells of adult A/J mice treated with anti-mu or anti-delta antibodies and also with purified B cell subsets of unimmunized adult A/J mice and on neonatal spleen cells. It appears that the memory (CRI-A) idiotype is selected into the HSA(low) B cell subset before antigen arrival.

The effect of social environment on the immune response of female common voles in matriarchal laboratory groups.

We used the hemagglutination test to investigate differences in the specific immune response to sheep red blood cells (SRBC) of female common voles living in matriarchal groups. The applied test proved to be a useful tool for studying the effect of the social environment on the immune response in small mammals. The required blood sampling method did not affect reproductive traits. Young female common voles showed a higher immune response than their mothers, which could have been caused by their age and/or by the reproductive and social dominance of their mothers. In non-breeding groups, the lower immune response of mothers could be attributed to their increased activity in advertising their dominance thus leading to an energy reallocation with consequent immunosuppression. Social stress, caused by crowded conditions, can lower the immune response and the growth of young females, which cannot leave the dams' proximity. The results are discussed regarding their relevance to the population regulation of the common vole and the spread of diseases to humans.

Molecular and cellular basis of the altered immune response against arsonate in irradiated A/J mice autologously reconstituted.

The humoral immune response to arsonate (Ars) in normal A/J mice is dominated in the late primary and particularly in the secondary response by a recurrent and dominant idiotype (CRIA) which is encoded by a single canonical combination of the variable gene segments: VHidcr11-DFL16.1-JH2 and Vkappa10-Jkappa1. Accumulation of somatic mutations within cells expressing this canonical combination or some less frequent Ig rearrangements results in the generation of high-affinity antibodies. By contrast, in partially shielded and irradiated A/J mice (autologous reconstitution) immunized with Ars-keyhole limpet hemocyanin (KLH), both the dominance of the CRIA idiotype and the affinity maturation are lost, whereas the anti-Ars antibody titer is not affected. To understand these alterations, we have analyzed a collection of 27 different anti-Ars hybridomas from nine partially shielded and irradiated A/J mice that had been immunized twice with Ars-KLH. Sequence analysis of the productively rearranged heavy chain variable region genes from those hybridomas revealed that (i) the canonical V(D)J combination was rare, (ii) the pattern of V(D)J gene usage rather corresponded to a primary repertoire with multiple gene combinations and (iii) the frequency of somatic mutations was low when compared to a normal secondary response to Ars. In addition, immunohistological analysis has shown a delay of 2 weeks in the appearance of full blown splenic germinal centers in autoreconstituting mice, as compared to controls. Such a model could be useful to understand the immunological defects found in patients transplanted with bone marrow.

Monitoring of a long survival myeloma patient.

Monitoring with anti-idiotypic sera has been applied to identify tumoral cells in a myeloma patient still alive in complete remission 9 years after diagnosis. Monoclonal plasma cells displayed a labeling index that decreased in complete remission below 1%. The great majority of B lymphocytes belonged to the tumoral clone even in complete remission and were therefore not affected by conventional chemotherapy. Some aspects of this myeloma patient are discussed in the light of these immunologic and kinetic findings. In addition, it is suggested that the therapeutic management of the complete remission should be re-examined, by considering a lymphocytolytic therapy.

Reduced tumor growth after low-dose irradiation or immunization against blastic suppressor T cells.

Suppressor T cells have been shown to be much more radiosensitive than other lymphoïd cells, and we have tried to reduce tumor growth by low-dose irradiation. Syngeneic DBA/2 mice received whole-body irradiation (150 rads; 1 rad = 0.01 J/kg) 6 days after P815 tumor inoculation. Tumor growth is significantly reduced in mildly irradiated mice. We also attempted to reduce syngeneic tumor growth by raising immunity against suppressor T cells in two different systems. DBA/2 mice were immunized against splenic T cells collected after disappearance of cytotoxicity and then injected with P815 tumor cells. These mice develop a very high primary cytotoxicity against P815 cells. C57BL/6 mice were immunized against blastic suppressor T cells, before injection of T2 tumor cells. Some of these mice reject the tumor and other develop smaller tumors than control mice. These results could be explained by the induction of antiidiotypic activity directed against the immunological receptors of suppressor T lymphocytes, because immunization with blastic suppressor T cells from mice bearing the T2 tumor does not modify the growth of another tumor, T10.

Idiotypic lymphocytes in human monoclonal gammopathies.

We have studied seven human monoclonal gammopathies using anti-idiotypic sera. In benign and malignant gammopathies, we have observed a similar number of B lymphocytes bearing idiotypic specificities also found on the monoclonal protein. These observations suggest that the plasma cell population is only a phenotypic expression of a tumoral event occurring in a B lymphocytes precursor which can still completely differentiate. In four myeloma patients and one benign monoclonal gammopathy, we also observed T lymphocytes bearing receptors idiotypically cross-reactive with the monoclonal protein. The values ranged from 1.8 to 8.0% within the purified T-cell population. In a first hypothesis, these T lymphocytes can belong to the tumoral clone itself. The tumoral event must occur at the level of a common precursor not yet determined to B or T pathway of differentiation. In a second hypothesis, these T lymphocytes are not cancerous but are induced by a strong perturbation of the idiotypic network, due to the enormous amount of the idiotypic B-cell tumoral subset.

Synthesis of antibodies and immunoglobulins bearing recipient allotypic markers and donor idiotypic specificities in irradiated rabbits grafted with allogeneic cells from hyperimmune donors.

Irradiated rabbits were grafted with a mixture of bone marrow, lymph node and spleen cells from donors hyperimmunized against TMV. Recipient and donors were characterized by different a allotypic specificities. Antibodies synthesized in the recipients display allotypic markers from the recipients but idiotypic specificities cross-reactive with those of donor antibodies. The results show that the differentiation of new host B cells is influenced by the presence of donor memory cells and are interpreted in the light of network concepts.

Synthesis of high affinity antibodies in irradiated rabbits grafted with allogeneic cells from hyperimmune donors.

Irradiated rabbits grafted with allogeneic lymph node, spleen and bone marrow cells from a donor rabbit hyperimmunized against TMV synthesize high affinity antibodies, displaying mainly recipient allotypic specificities, after antigen boosting. By contrast, recipient rabbits from non-immune donors synthesize antibodies of lower affinity. It is suggested that the differentiation of new emerging host B cells is specifically influenced by the presence of donor-memory cells.

Sharing of idiotypic specificities between different antibody populations from an individual rabbit.

Rabbits hyperimmunized with tobacco mosaic virus synthesize very heterogeneous antibodies. Despite this, specific anti-idiotypic sera recognizing a large part (70%) of these antibodies can be raised in rabbits matched for allotypic specificities a1, a2, a3, b4, b5, b6, c7, and b9. Different rabbits synthesize antibodies with different idiotypic specificities. However, in the serum of a single rabbit antibody fractions of different isoelectric pH share some idiotypic specificities. The results show that, at least in certain cases, antibodies against one antigen are not simply a random collection of immunoglobulin which happen to fit with this antigen, but that some definite relationship exists between the products of different clones which have been activated by antigen. These findings are discussed in the light of network concepts of the immune system.