The interleukin-2 receptor gamma chain (IL-2R gamma) is a necessary component of functional IL-2 receptors. IL-2R gamma mutations result in X-linked severe combined immunodeficiency (XSCID) in humans, a disease characterized by the presence of few or no T cells. In contrast, SCID patients with IL-2 deficiency and IL-2-deficient mice have normal numbers of T cells, suggesting that IL-2R gamma is part of more than one cytokine receptor. By using chemical cross-linking, IL-2R gamma was shown to be physically associated with the IL-7 receptor. The presence of IL-2R gamma augmented both IL-7 binding affinity and the efficiency of internalization of IL-7. These findings may help explain the defects of XSCID. Given its role in more than one cytokine receptor system, the common gamma chain (gamma c) is proposed as the designation for IL-2R gamma.

/pdf/interleukin-2-receptor-gamma-chain-a-functional-component-of-3q4z6f908z.pdf

Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor

The abundance and activation of macrophages in the inflamed synovial membrane/pannus significantly correlates with the severity of rheumatoid arthritis (RA). Although unlikely to be the 'initiators' of RA (if not as antigen-presenting cells in early disease), macrophages possess widespread pro-inflammatory, destructive, and remodeling capabilities that can critically contribute to acute and chronic disease. Also, activation of the monocytic lineage is not locally restricted, but extends to systemic parts of the mononuclear phagocyte system. Thus, selective counteraction of macrophage activation remains an efficacious approach to diminish local and systemic inflammation, as well as to prevent irreversible joint damage.

/pdf/macrophages-in-rheumatoid-arthritis-4w937ok76z.pdf

Macrophages in rheumatoid arthritis

Objective. To define variations in the cellular infiltrate and in the expression of monokines in synovial tissue (ST) from rheumatoid arthritis (RA) patients with different durations of disease and different levels of disease activity.



Methods. The immunohistologic features of synovial biopsy specimens from 31 patients with early RA ( 5 years) were compared. The possible associations between these features and local disease activity, as measured by the score for pain in the biopsied knee joint, were also evaluated.



Results. The immunohistologic features were not dependent on disease duration. We found a positive correlation between the scores for knee pain and the semiquantitative scores for the number of macrophages, as well as the expression of interleukin-6 and tumor necrosis factor α, whereas the correlation with the scores for CD4+ T cells was negative. Multivariate analysis showed that these correlations were highly statistically significant (P < 0.003).



Conclusion. The results do not support the view that inflammatory mechanisms in the synovial tissues of RA patients differ between early and late stages of the disease. The findings presented here are consistent with the concept that early RA is the result of a synovitis process of longer duration and that macrophage-derived cytokines play an important role in maintaining the clinical signs of inflammation.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.1780400206

Analysis of the synovial cell infiltrate in early rheumatoid synovial tissue in relation to local disease activity

Dendritic cells (DCs; 1) have been purified from mouse spleen in good yield. Spleen cell suspensions were floated on dense bovine plasma albumin (BPA) columns, and the low density fraction was adhered to glass (2). The adherent cells consisted of DCs and immature macrophages most of which eluted in a viable state from the culture dish after overnight incubation. The macrophages were then removed by selective rosetting with opsonized erythrocytes and recentrifugation on dense BPA. This protocol resulted in a purified DC fraction, containing 1--3 X 10(5) DCs/spleen, which was homogeneous and distinctive in its properties. All cells exhibited the phase contrast and transmission electron microscopy (EM) cytologic features that were previously described for freshly isolated adherent DCs. By scanning EM, most purified DCs exhibited a remarkable array of bulbous protrusions of varying length and shape, unlike any other lymphoid cell. All DCs expressed surface Ia and other major histocompatibility complex (MHC)- linked alloantigens. DCs, however, lacked surface Ig and T-cell antigens, and did not bind or interiorize opsonized erythrocytes. Purified DCs have been maintined in vitro for 3 days. Recovery of cultured purified cells was 70% or more of starting cell numbers. When [3H]uridine-tagged DCs were mixed with nonlabeled heterogeneous spleen cells, 70--80% of the labeled DCs were recovered as viable cells 2--3 days later. Purified DCs did not readhere to tissue culture surfaces and did not proliferate, even when cultured with mitogenic doses of concanavalin A and lipopolysaccharide. Finally, DCs did not change their cytologic or surface properties after 3 days of culture. These observations extend the evidence that DCs are a novel cell type and provide useful properties and techniques for their further study.

Lymphoid organs of mice. V. Purification of spleen dendritic cells, new surface markers, and maintenance in vitro.

Both tumor necrosis factor alpha (TNF-alpha) and transforming growth factor beta (TGF-beta) are found in synovial fluid from arthritic joints of humans and of rodents with experimental arthritis. The role of endogenously produced TGF-beta and TNF in the pathogenesis of collagen type II-induced arthritis (CIA) in DBA/1 mice was examined by determining the effect of neutralizing monoclonal antibodies to these factors on the course of the disease. Endogenously produced as well as systemically administered TGF-beta 1 and TNF-alpha had opposite effects, since TGF-beta 1 and anti-TNF protected against CIA, whereas anti-TGF-beta and TNF-alpha increased CIA incidence and/or severity. Intraperitoneally injected TGF-beta 1 at a dose of 2 micrograms per day for 14 days significantly ameliorated arthritis, even when started at the time of arthritis development, although it did not reverse established disease. The resistance to CIA induction caused by a prior intravenous injection of collagen type II was not significantly influenced by the simultaneous injection of TGF-beta 1, TNF-alpha, or interleukin 1 alpha. It is concluded that the endogenous production of TNF and TGF-beta is important in determining the course of CIA.

https://www.pnas.org/content/pnas/89/16/7375.full.pdf

Involvement of endogenous tumor necrosis factor alpha and transforming growth factor beta during induction of collagen type II arthritis in mice.

Immunohistochemical double-staining was performed on frozen sections from synovial biopsies obtained at arthroscopy from 22 patients with different kinds of synovitis. Not only in specimens from patients with rheumatoid arthritis and seronegative chronic polyarthritis, but also in those from patients with synovitis due to psoriasis, trauma, or crystals, were seen many alpha Leu-1-positive T lymphocytes--in most cases predominantly of the alpha Leu-3a-positive T "helper" cell type--in close contact with HLA-DR-positive macrophages/dendritic cells. Presence of many HLA-DR-positive, often OKM1-negative, and irregular sublining cells characterized all forms of chronic arthritis.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.1780261104

Phenotypic characterization of synovial tissue cells in situ in different types of synovitis.

Normal and rheumatoid synovial cells have been analyzed in frozen sections and in suspension. HLA-DR-expressing, macrophage-like cells are demonstrated in normal synovial intima and in rheumatoid tissue. Suspended normal synoviocytes equaled peripheral blood non-T lymphocytes as stimulators of mixed lymphocyte reactions, whereas adherent rheumatoid synovial cells were extremely efficient as such stimulators and in presenting soluble antigens to autologous T lymphocytes. This HLA-DR-dependent T lymphocyte regulation might provide a cellular basis for the HLA-D haplotype-arthritis associations.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.1780250502

Immune functions of human synovial cells. phenotypic and t cell regulatory properties of macrophage-like cells that express hla–dr

This study describes the opposing effects that interleukin (IL) 4 exerts on the B cell stimulatory factor (BSF-MP6) and IL 2-dependent proliferation and differentiation of cells of one selected B-type chronic lymphocytic leukemia cell clone (I83), which depend on the nature of the activation inducer. In I83 cells activated by a 1-h pulse of 12-O-tetradecanoylphorbol 13-acetate, the BSF-MP6-dependent DNA synthesis was strongly enhanced by 50-100 U/ml of recombinant IL 4. Recombinant IL 2 stimulation was necessary only when a suboptimal dose of BSF-MP6 was used. The differentiation was also markedly enhanced by IL 4 as measured by quantitation of IgM secretion both at the population (enzyme-linked immunosorbent assay analyses of the supernatant) and single-cell level (enzyme-linked immunospot technique), by morphological examination of the maturation stage and flow cytometric analysis of differentiation-associated surface antigens (CD11c, FMC7, PCA-1 and CD38). No Ig isotype switch was found. In contrast, DNA synthesis and differentiation of I83 cells, activated by Staphylococcus aureus Cowan strain I (SAC) and co-stimulated with BSF-MP6 plus IL 2, were strongly inhibited by IL 4, both when it was added simultaneously with SAC or after 2 days of SAC exposure. Analysis of the cell-cycle progression of SAC and BSF-MP6 plus IL 2 and IL 4-stimulated cells by acridine orange staining and fluorescence-activated cell sorter (FACS) analysis demonstrated an arrest of a minor cell population in G0 and a block of the transition of G1 cells to S phase. Neither the enhancing nor the inhibitory effect of IL 4 on the proliferation and differentiation of I83 cells was an indirect effect via IL 4-induced activation of contaminating T cells, monocytes or natural killer cells, as shown by experiments where these cell types were depleted by FACS sorting. Furthermore the expression of CD23 and CD25 was not inhibited by IL 4. The results thus demonstrate contrasting biological effects of IL 4 on clonal leukemic B cells depending on the nature of the activation and progression stimuli. This adds to the emerging picture of a very complex cytokine and cell-to-cell contact-mediated regulation of the activation and subsequent growth and/or differentiation of human B cells.

Interleukin 4 strongly augments or inhibits DNA synthesis and differentiation of B‐type chronic lymphocytic leukemia cells depending on the costimulatory activation and progression signals

Christer Sundström

Papers

Phenotypic characterization of synovial tissue cells in situ in different types of synovitis.

Immune functions of human synovial cells. phenotypic and t cell regulatory properties of macrophage-like cells that express hla–dr

Interleukin 4 strongly augments or inhibits DNA synthesis and differentiation of B‐type chronic lymphocytic leukemia cells depending on the costimulatory activation and progression signals

prognosis in chronic lymphocytic leukemia CD38 expression is a poor predictor for VH gene mutational status and

mantle cell lymphoma Mutated VH genes and preferential VH3-21 use define new subsets of