Allergic pathology is a topical problem in modern medicine. There is a steady increase in allergic diseases around the world. The term “food allergy” refers to adverse reactions associated with a specific immune response to food products. Food sensitization develops, as a rule, in the first years of life. In most cases, pronounced allergic reactions to food products disappear as they grow older, which is relevant for most allergens, such as cow’s milk allergens, chicken eggs, cereals, etc. This phenomenon can be explained by the induction of oral tolerance. Food allergy (PA) is mainly manifested by skin and intestinal syndromes. In this heterogeneous group of diseases, IgE–dependent and non–IgE–dependent PA and mixed type are distinguished taking into account the mechanism of development (Table). Possible non–IgE mechanisms include type II and type IV reactions according to the classification, as well as the recently described variant of immediate hypersensitivity with formation of free kappa– and lambda–chain immunoglobulin lungs (SLC).
As a rule, IgE–dependent PA is characterized by acute onset, which is expressed in the form of anaphylaxis in the most severe manifestation. Non–IgE–dependent PA is characterized by gradual onset and long symptoms, mainly from the gastrointestinal tract. The peculiarities of development of non–IgE–associated food reactions predispose to their diverse course, similar to the hypersensitivity of the immediate type. At an early age, non–IgE–mediated PA with frequent symptoms of gastrointestinal damage prevails, with clinical manifestations ranging from infant colic, repeated vomiting, constipation to bloody diarrhoea and hypovolemia. However, life–threatening complications in non–IgE–dependent PA are rare and, in most cases, the prognosis in this form of PA is favorable.
The pathophysiological basis of non–IgE–conditioned allergic reactions induced by dietary proteins is not sufficiently clear. It is assumed that stimulation of T–cells of the intestinal mucosa, imbalance of FNO– and FNO– with hyperproduction of the latter and production of IL–5 leading to migration of eosinophils are important in these processes. Non–IgE–dependent immune response may also lead to activation of mastocytes. The development of immune response, as in the case of IgE–mediated allergy, is accompanied by failure of food tolerance mechanisms.
The pathophysiological mechanisms underlying the different types of PAs differ significantly. When a food allergen first enters the body, e.g. by oral or percutaneous route, the antigenic determinants of the allergen are presented to sensitive cells (e.g. dendritic cells). Naive T–helpers are activated, which stimulates the functional activity of B–lymphocytes in local lymph nodes, usually in peyer plaques and mesenteric lymph nodes, and triggers the mechanisms of immune tolerance or sensitization. Dendritic cells play a central role in these events. At present, the processes regulating these mechanisms are not yet fully characterized. The presence of retinoic acid and the production of anti–inflammatory IL–10 and TFR– cytokines play an important role in food tolerance, which affects the formation of tolerogenic Treg cells. B cells are able to produce sIgA, which has neutralizing antigenic activity. If the necessary conditions do not arise for the induction of tolerance, the food allergen is sensitized. Epithelial cytokines are released: IL–33, thymic stromal lymphopoietin (TSLP) and IL–25, which indirectly stimulates differentiation of Th0 by Th2–type. The resulting Th2–cells secrete a number of allergic inflammatory cytokines, such as IL–5, responsible for eosinophil chemotaxis, as well as IL–4 and IL–13, which cause switching to the production of IgE–isotype in B–cells. sIgE bind to Fc–Gamma–RI on basophilic and mast cell surfaces. Subsequent contact with this food allergen leads to activation and degradation of these cells and release of proinflammatory factors. Studies indicate that the food antigen should be included in the general circulation for an immune response to occur. This is how the IgE–associated allergic immune response is implemented.
The pathway of activation of mast cells carried out in the process of IgE–dependent immune response is the most studied. However, it has been established that there is another way in which SLC is involved. This method can play a role in non–IgE–mediated allergic pathology.
In the 2000s and 2010s, T. Groot Kormelink et al. (2009) it was found that mast cells play a role in these processes, which have been subjected to partial degradation. As a result of the study of mediators, which led to partial degranulation, a factor was revealed, which showed high specificity, comparable with the specificity of antibodies, leading to the formation of B–cells in the sample. Further studies have shown that there is an alternative way to activate mast cells: polyclonal immunoglobulin lungs in combination with antigen activate mast cells directly, without the participation of a complement, similar to the way IgE–antibodies do it. In vivo experiments, specific local skin sensitivities to haptene–specific free light immunoglobulin chains were induced. This sensitivity was dose–dependent and comparable to the response after sensitization to haptene–specific IgE. The ability of heavy immunoglobulin chains to activate mast cells was not shown in the experiments.
Free immunoglobulin lungs are defined as 22–27 and 44–55 kDa, which means that they are not associated covalently with heavy chains, but are present in free form in the form of mono– and dimeric conformation, respectively. It has been established that SLC–dependent hypersensitivity is mediated by mast cells, although the mechanism by which SLC performs its function has not yet been determined and the specific receptor to them is not fully characterized. SLCs are produced by B–cells. Two types of light chains form in mammalian cells: the kappa and the lambda. Their ratio is specific for each species, and the products are independent from the production of heavy chains. The norm is characterized by 10–40% hyperproduction of light chains in relation to heavy ones. In extracellular space there is a pool of free light chains. Regulation of light chain products is still under study!
SLCs are determined in various biological fluids, including serum and urine, in the prevailing amount in the form of monomers, and there are dimeric and polymeric forms. The concentration of SLC is low at birth and gradually increases with age. Normal levels of SLC in serum in healthy adults are about 3.3–19.4 mg/l for and 5.7–26.3 mg/l for , but they are highly dependent on equipment and calibration standards. The content and ratio of monoclonal SLC and SLC in blood serum is an important diagnostic criterion for monoclonal gammapathies. Like heavy chains, light chains contain a C–terminal constant region and an N–terminal variable region (with which the antigen binds). They are derived from SLC by kidneys, captured by the cells of the proximal tubular epithelium. Tumors of antibody–producing plasma cells in urine secrete an increased number of free light chains of immunoglobulins, which leads to impaired renal function.
Recent studies indicate a significant role of SLC in allergic pathology. SLC showed variable affinity. In the experiments, there were difficulties in identifying specific SLC in biological fluids, which may be due to their low affinity, low concentration and short period of life.
Diet therapy is an integral part of the treatment and, according to clinical recommendations, is prescribed for the long term. The algorithm of diagnosis includes a detailed history collection, analysis of the clinical picture of the disease, additional laboratory methods of detection of sensitization and conducting elimination and provocation tests. In this regard, the requirements for accuracy of diagnostics are increasing. Identification of IgE–dependent PA, along with the presence of a characteristic clinical pattern, is facilitated by a number of standard methods, such as skin prick–tests and determination of sIgE levels. According to Diagnosis and rationale for action against cow’s milk allergy (DRACMA), the normal level of IgE–specific cow’s milk proteins and negative skin prick–test (papula< 3 mm) with cow’s milk in children with a proven allergy to cow’s milk proteins (elimination–provocative effect) indicate in favor of non–IgE–mediated allergy.
In the non–IgE–conditioned PA form, these methods are not informative. In addition, the determination of sIgE in serum, unfortunately, does not always allow the practitioner to accurately identify the spectrum of sensitization, as both false negatives and false positives are possible. Also, elimination and provocation tests (oral food provocation test (OFPT), ideally double placebo–controlled food provocation test (DFPT) are widely used for diagnostic purposes, which are useful in detecting PA as a whole, but do not allow to differentiate between PA forms. In addition, our country lacks a validated protocol for conducting a provocative test, which is permitted in wide clinical practice.In the non–IgE–conditioned PA form, these methods are not informative. In addition, the determination of sIgE in serum, unfortunately, does not always allow the practitioner to accurately identify the spectrum of sensitization, as both false negatives and false positives are possible. Also, elimination and provocation tests (oral food provocation test (OFPT), ideally double placebo–controlled food provocation test (DFPT) are widely used for diagnostic purposes, which are useful in detecting PA as a whole, but do not allow to differentiate between PA forms. In addition, our country lacks a validated protocol for conducting a provocative test, which is permitted in wide clinical practice.
At the moment, there are no universally recognized methods to diagnose non–IgE–dependent PA. The absence of such methods makes it difficult to study this type of PA. In this connection, the determination of specific free light chains of immunoglobulins is a promising method of laboratory diagnostics of food sensitization.
In the results of the study published earlier by us SLC in 43 children of the first year of life with an allergy to cow’s milk proteins (ABKM) in the form of severe skin and/or gastrointestinal manifestations, a reliable decrease in the level of – and –chains (p = 0.02) was shown in children against the background of elimination and use of the amino acid mixture (Neocate LCP). It is in children with gastrointestinal manifestations of ABKM that a reliable decrease of SLC was observed against the background of using the amino acid mixture in the diet.
Food allergy is a polyethylological disease based on a genetic predisposition to certain immune responses. The decoding of IgE–dependent and non–IgE–dependent mechanisms of food allergy allows the doctor to identify the spectrum of sensitization, predict the duration of elimination and the time of diet expansion. Lack of laboratory methods for confirmation of non–IgE–dependent mechanisms of allergic reaction significantly complicates the achievement of the effect of treatment. Free ( and ) immunoglobulin light chains, according to the latest scientific data, can participate in the pathogenesis of non–IgE–dependent allergic reactions by direct activation of mast cells. Immunoenzyme analysis in the determination of SLC in the blood serum of patients with food allergies is currently a promising method of laboratory diagnosis of sensitization. Further research is required on SLC in children with food allergies in order to study their clinical significance.