Interleukin-4, Serum

Serum

0.5 mL

0.3 mL (Note: This volume does not allow for repeat testing.)

Red-top tube or gel-barrier tube

This test is used for the measurement of Interleukin-4 (IL-4) levels in serum.

This test was developed and its performance characteristics determined by Labcorp. It has not been cleared or approved by the Food and Drug Administration.

Enzyme-linked immunosorbent assay (ELISA)

Cytokines are low-molecular-weight intercellular signaling molecules that are produced de novo in response to an immune stimulus.^1-3 They regulate immune cell homeostasis by mediating innate and acquired immunity and inflammation in human health and disease. They generally (although not always) act over short distances and short time spans and at very low concentrations. They act by binding to specific membrane receptors, which then signal the cell via second messengers, often tyrosine kinases, to alter its behavior. Responses to cytokines include increasing or decreasing expression of membrane proteins (including cytokine receptors), proliferation and secretion of effector molecules. It is common for different cell types to secrete the same cytokine or for a single cytokine to act on several different cell types (pleiotropy). Cytokines are redundant in their activity, meaning similar functions can be stimulated by different cytokines. Cytokines are often produced in a cascade, as one cytokine stimulates its target cells to make additional cytokines. Cytokines can also act synergistically (two or more cytokines acting together) or antagonistically (cytokines causing opposing activities).

T Helper cells (T_H cells), also known as CD4+ cells or CD4-positive cells, play an important role in the adaptive immune system. They are essential in B cell antibody class switching,^4,5,6 breaking cross-tolerance in dendritic cells, activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. IL-4 acts on both B and T cells. It is a B-cell growth factor and causes IgE and IgG1 isotype selection.⁷ It causes T_H2 differentiation and proliferation, and it inhibits IFN gamma-mediated activation on macrophages. It promotes mast cell proliferation in vivo.⁸ Naive T_H cells (T0 cells) differentiate into two major T_H helper subtypes, referred to as T_H1 and T_H2 cells. T_H2 cells produce interleukin-4 (IL-4) along with IL-5 and IL-13.^2,9 Peripheral T_H0 cells, upon recognition of antigenic peptides by the T cell receptor (TCR), migrate into lymphoid tissues and functionally differentiate into different T_H cell subsets.¹⁰ IL-4 promotes T_H2 immune response by inducing the differentiation of T_H0 cells to T_H2 cells in a positive feedback loop.¹¹ IL-4 induces T_H2 cell differentiation in an autocrine manner at inflammatory sites.¹² T_H2 cells gain full effector capacity in tissues by interacting with various local cells, including innate lymphoid cells and neurons, which produce T_H2-promoting factors in response to allergens, helminths and other stimuli.^2,10

In addition to T_H2 cells, mast cells, eosinophils and basophils produce IL-4.^13-15 Eosinophils produce IL-4 in the very early stage of the immune response in lymph nodes and tissues and can induce T_H2 differentiation by antigen presentation to CD4+ T cells.¹⁰ Fibroblasts play an important role in normal tissue repair and the induction of fibrosis by directly depositing extra cellular matrix in response to various growth factors and cytokines, including T_H2 cytokines.¹⁰ Macrophages that are activated by IL-4 and IL-13 have been reported to induce fibrosis by various mechanisms.

IL-4 is the most common cytokine produced by T_H2 lymphocytes and the key cytokine that regulates T_H2 cell polarization.^12,16 In addition, IL-4/IL-4R signaling promotes B cell proliferation and stimulates immunoglobulin class-switching to IgE antibody, the major antibody in allergic reactions.^12,16 Production of these cytokines by T_H2 lymphocytes and other cells accounts for the activation of the mast cells, basophiles, eosinophiles and smooth muscle cell contraction as well as stimulation of B cell differentiation into IgE-producing plasma cells, thus promoting several allergic reactions including allergic rhinitis, anaphylaxis, atopic dermatitis and asthma.^12,16,17 T_H2 cells are often observed in tissues in allergic patients and are known to play critical roles in the pathogenesis of allergic diseases.^9,12,18-22 Allergic diseases are characterized by aberrant activation of T_H2 cells in response to innocuous environmental proteins (allergens)²³ and subsequent production of Type 2 cytokines at sites of allergic inflammation.^24,25 These reactions involve inflammatory mediators released in the early-phase reaction by mast cells and basophils, and allergen-specific T_H2 lymphocytes.²⁶ T_H2 cells act synergistically with type 2 innate-like lymphoid cells activated during the acute phase. They recruit effector cells such as eosinophils, basophils, as well as other lymphocytes, to the site of allergen exposure.^27-29 IL-4, IL-5, and IL-13 drive T_H2 cells towards a specialized T_H2A phenotype associated with persistent allergy and high cytokine expression.^30,31

Asthma is a heterogeneous disease that can be classified into phenotypes and endotypes based upon clinical or biological characteristics.^13,32-34 IL-4, along with IL-13, plays a key role in T_H2 asthma.³² Over expression of IL-4 in asthmatics is associated with exacerbations, compromised lung function, airway remodeling and airway epithelium injury.³⁵ Approximately 50% of mild-to-moderate asthma and a large portion of severe asthma is associated with T_H2-dependent inflammation.³³ IL-4 mediates pro-inflammatory functions in asthma, including induction of the expression of vascular cell adhesion molecule-1 (VCAM-1), promotion of eosinophil transmigration across endothelium and mucus secretion.^36,37 T_H2 inflammation is characterized by elevations in absolute peripheral or sputum eosinophil counts and levels of IgE (total and allergen-specific) and fractional exhaled nitric oxide, which serve as biomarkers for the presence of this type of inflammation.¹³ Compared with healthy controls, children and adults with asthma have higher serum levels of IL-4,^38,39 and higher IL-4 levels may differentiate individuals with atopic asthma from those with nonatopic asthma.^38,39 Persistence of asthma in children and adults may be predicted by elevated levels of IL-4.^19,20

IL-4 regulates the protective immune response against helminths and other extracellular parasites.^3,7 Plasma levels of IL-4 have been reported to be elevated in patients with eosinophilic esophagitis, indicating the role of adaptive T_H2 immunity in this disease.⁴⁰ A meta-analysis found that elevated IL-4 was strongly associated with acute respiratory distress syndrome mortality.⁴¹

There have been extensive clinical trials targeting IL-4 for the treatment of asthma.²⁴ Modulation of IL-4 signaling⁴² represents an important therapeutic approach to target the drivers of allergy and asthma.^18,42-45 Dupilumab targets the shared receptor for IL-4 and IL-13 and is approved for treatment of atopic dermatitis and asthma.² Dupilumab has been shown to provide efficacy in the treatment of moderate-to-severe atopic dermatitis, allergic asthma, chronic rhinosinusitis and eosinophilic esophagitis, all known to be driven largely by type 2 inflammation.^18,43-45

IL-4 and IL-13 produced by T_H2 cells activate macrophages and epithelial cells and enhance the production of extracellular matrix, an element crucial for tissue repair.¹⁰ However, when the tissue repair process becomes chronic, excessive or uncontrolled, it may induce the development of pathological fibrosis in various organ systems.¹⁰ It was recently shown that T_H2 cells include pathogenic T_H2 (Tpath2) cells that highly express the receptor for IL-33 (a cytokine that is released during tissue injury) and produce large amounts of IL-5.^9,10