In the mid-1980s, Mosmann, Coffman, and their colleagues discovered that murine CD4+ helper T-cell clones could be distinguished by the cytokines they synthesized. The isolation of human Th1 and Th2 clones by Romagnani and coworkers in the early 1990s has led to a large number of reports on the effects of Th1 and Th2 on the human immune system. More recently, cells other than CD4+ T cells, including CD8+ T cells, monocytes, NK cells, B cells, eosinophils, mast cells, basophils, and other cells, have been shown to be capable of producing "Th1" and "Th2" cytokines. In this review, we examine the literature on human diseases, using the nomenclature of type 1 (Th1-like) and type 2 (Th2-like) cytokines, which includes all cell types producing these cytokines rather than only CD4+ T cells. Type 1 cytokines include interleukin-2 (IL-2), gamma interferon, IL-12 and tumor necrosis factor beta, while type 2 cytokines include IL-4, IL-5, IL-6, IL-10, and IL-13. In general, type 1 cytokines favor the development of a strong cellular immune response whereas type 2 cytokines favor a strong humoral immune response. Some of these type 1 and type 2 cytokines are cross-regulatory. For example, gamma interferon and IL-12 decrease the levels of type 2 cytokines whereas IL-4 and IL-10 decrease the levels of type 1 cytokines. We use this cytokine perspective to examine human diseases including infections due to viruses, bacteria, parasites, and fungi, as well as selected neoplastic, atopic, rheumatologic, autoimmune, and idiopathic-inflammatory conditions. Clinically, type 1 cytokine-predominant responses should be suspected in any delayed-type hypersensitivity-like granulomatous reactions and in infections with intracellular pathogens, whereas conditions involving hypergammaglobulinemia, increased immunoglobulin E levels, and/or eosinophilia are suggestive of type 2 cytokine-predominant conditions. If this immunologic concept is relevant to human diseases, the potential exists for novel cytokine-based therapies and novel cytokine-directed preventive vaccines for such diseases.

Type 1 and type 2 cytokine dysregulation in human infectious, neoplastic, and inflammatory diseases.

IL-13 is an immunoregulatory cytokine secreted predominantly by activated T(H)2 cells. Over the past several years, it has become evident that IL-13 is a key mediator in the pathogenesis of allergic inflammation. IL-13 shares many functional properties with IL-4, stemming from the fact that they share a common receptor subunit, the alpha subunit of the IL-4 receptor (IL-4Ralpha). Characterization of IL-13-deficient mice, IL-4-deficient mice, and IL-4 receptor alpha-deficient (IL-4Ralpha(-/-)) mice have demonstrated nonredundant roles for IL-13. IL-13 mediates its effects by interacting with a complex receptor system comprised of IL-4Ralpha and two IL-13 binding proteins, IL-13Ralpha1 and IL-13Ralpha2. IL-13 receptors are expressed on human B cells, basophils, eosinophils, mast cells, endothelial cells, fibroblasts, monocytes, macrophages, respiratory epithelial cells, and smooth muscle cells. However, functional IL-13 receptors have not been demonstrated on human or mouse T cells. Thus unlike IL-4, IL-13 does not appear to be important in the initial differentiation of CD4 T cells into T(H)2-type cells but rather appears to be important in the effector phase of allergic inflammation. This is further supported by many in vivo observations, including that administration of IL-13 resulted in allergic inflammation, tissue-specific overexpression of IL-13 in the lungs of transgenic mice resulted in airway inflammation and mucus hypersecretion, IL-13 blockade abolished allergic inflammation independently of IL-4, and IL-13 appears to be more important than IL-4 in mucus hypersecretion. Given the importance of IL-13 as an effector molecule, regulation at the level of its receptors might be an important mechanism of modulating IL-13 responses and thus propagation of the allergic response. Accordingly, IL-13 is an attractive, novel therapeutic target for pharmacologic intervention in allergic disorders. This review will summarize the current understanding of the IL-13 receptors and signaling pathways, emphasizing recent observations.

IL-13 receptors and signaling pathways: An evolving web

Patients with human severe combined immunodeficiency (SCID) can be divided into those with B lymphocytes (B + SCID) and those without (B − SCID) Although several genetic causes are known for B + SCID, the etiology of B − SCID has not been defined Six of 14 B − SCID patients tested were found to carry a mutation of the recombinase activating gene 1 ( RAG-1 ), RAG-2 , or both This mutation resulted in a functional inability to form antigen receptors through genetic recombination and links a defect in one of the site-specific recombination systems to a human disease

https://science.sciencemag.org/content/sci/274/5284/97.full.pdf

RAG Mutations in Human B Cell-Negative SCID

Since its discovery two decades ago, the activation of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway by numerous cytokines and growth factors has resulted in it becoming one of the most well-studied intracellular signalling networks. The field has progressed from the identification of the individual components to high-resolution crystal structures of both JAK and STAT, and an understanding of the complexities of the molecular activation and deactivation cycle which results in a diverse, yet highly specific and regulated pattern of transcriptional responses. While there is still more to learn, we now appreciate how disruption and deregulation of this pathway can result in clinical disease and look forward to adoption of the next generation of JAK inhibitors in routine clinical treatment.

/pdf/biology-and-significance-of-the-jak-stat-signalling-pathways-37tt3bwlkg.pdf

Biology and significance of the JAK/STAT signalling pathways.

Interleukins 4 (IL-4) and 13 (IL-13) have been found previously to share receptor components on some cells, as revealed by receptor cross-competition studies. In the present study, the cloning is described of murine NR4, a previously unrecognized receptor identified on the basis of sequence similarity with members of the hemopoietin receptor family. mRNA encoding NR4 was found in a wide range of murine cells and tissues. By using transient expression in COS-7 cells, NR4 was found to encode the IL-13 receptor alpha chain, a low-affinity receptor capable of binding IL-13 but not IL-4 or interleukins 2, -7, -9, or -15. Stable expression of the IL-13 receptor alpha chain (NR4) in CTLL-2 cells resulted in the generation of high-affinity IL-13 receptors capable of transducing a proliferative signal in response to IL-13 and, moreover, led to competitive cross-reactivity in the binding of IL-4 and IL-13. These results suggest that the IL-13 receptor alpha chain (NR4) is the primary binding subunit of the IL-13 receptor and may also be a component of IL-4 receptors.

https://www.pnas.org/content/pnas/93/1/497.full.pdf

Cloning and characterization of a binding subunit of the interleukin 13 receptor that is also a component of the interleukin 4 receptor

Function of the interleukin-2 (IL-2) receptor gamma-chain in biologic responses of X-linked severe combined immunodeficient B cells to IL-2, IL-4, IL-13, and IL-15.

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Function of the interleukin-2 (IL-2) receptor gamma-chain in biologic responses of X-linked severe combined immunodeficient B cells to IL-2, IL-4, IL-13, and IL-15.