The Enigmatic Nature of the TCR-pMHC Interaction: Implications for CAR-T and TCR-T Engineering.

The interaction of the T-cell receptor (TCR) with a peptide in the major histocompatibility complex (pMHC) plays a central role in the adaptive immunity of higher chordates. Due to the high specificity and sensitivity of this process, the immune system quickly recognizes and efficiently responds to the appearance of foreign and altered self-antigens. This is important for ensuring anti-infectious and antitumor immunity, in addition to maintaining self-tolerance. The most common parameter used for assessing the specificity of TCR-pMHC interaction is affinity. This thermodynamic characteristic is widely used not only in various theoretical aspects, but also in practice, for example, in the engineering of various T-cell products with a chimeric (CAR-T) or artificial (TCR-engineered T-cell) antigen receptor. However, increasing data reveal the fact that, in addition to the thermodynamic component, the specificity of antigen recognition is based on the kinetics and mechanics of the process, having even greater influence on the selectivity of the process and T lymphocyte activation than affinity. Therefore, the kinetic and mechanical aspects of antigen recognition should be taken into account when designing artificial antigen receptors, especially those that recognize antigens in the MHC complex. This review describes the current understanding of the nature of the TCR-pMHC interaction, in addition to the thermodynamic, kinetic, and mechanical principles underlying the specificity and high sensitivity of this interaction.

Autoimmune thyroiditis and exposure to iodine 131 in the Ukrainian cohort study of thyroid cancer and other thyroid diseases after the Chornobyl accident: results from the first screening cycle (1998-2000).

CONTEXT: Due to the Chornobyl accident, millions were exposed to radioactive isotopes of iodine and some received appreciable iodine 131 (131I) doses. A subsequent increase in thyroid cancer has been largely attributed to this exposure, but evidence concerning autoimmune thyroiditis (AIT) remains inconclusive. OBJECTIVE: The objective of the study was to quantify risk of AIT after 131I exposure. DESIGN/SETTING/PARTICIPANTS: Baseline data were collected from the first screening cycle (1998-2000) of a large cohort of radiation-exposed individuals (n = 12,240), residents of contaminated, iodine-deficient territories of Ukraine. Study individuals were under the age of 18 yr on April 26, 1986, and had thyroid radioactivity measurements made shortly after the accident. OUTCOMES: AIT was defined a priori based on various combinations of elevated antibodies to thyroid peroxidase (ATPO), TSH, and clinical findings; elevated ATPO were considered to be an indicator of thyroid autoimmunity. RESULTS: No significant association was found between 131I thyroid dose estimates and AIT, but prevalence of elevated ATPO demonstrated a modest, significant association with 131I that was well described by several concave models. This relationship was apparent in individuals with moderately elevated ATPO and euthyroid, thyroid disease-free individuals. CONCLUSIONS: Twelve to 14 yr after the Chornobyl accident, no radiation-related increase in prevalence of AIT was found in a large cohort study, the first in which 131I thyroid doses were estimated using individual radioactivity measurements. However, a dose-response relationship with ATPO prevalence raises the possibility that clinically important changes may occur over time. Thus, further follow-up and analysis of prospective data in this cohort are necessary.

[Mosaicism of the upper respiratory tract epithelium in liquidators of the Chernobyl accident]. / Mozaichnost' épiteliia verkhnikh dykhatel'nykh putei u likvidatorov posledstvii avarii na ChAES.

On the basis of findings from the structural analysis of 21 nasal mucosa biopsy specimens of patients with chronic rhinitis including 12 participants in liquidation of the consequences of the Chernobyl accident using morphometric methods, signs of morphofunctional insufficiency of the nasal epithelium are verified. Mechanisms of this phenomenon development are discussed.

[Invasion of microorganisms in bronchial mucosa of liquidators of the Chernobyl accident consequences]. / Invaziia mikroorganizamov v slizistuiu obolochku bronkhov likvidatorov posle destvii avarii na Chernobyl'skoi AES.

Bronchial bioptates of 97 liquidators of the Chernobyl accident consequences with chronic bronchitis and 23 patients of control nosological group as well as sputum (174 persons) and BAL (22 persons) of liquidators with chronic obstructive lung disease (COLD) were studied to define pathogenic role of automicroflora in the development of lung diseases. Such methods as electron microscopy, immunohistochemistry and microbiology were used. The revealed invasion of microorganisms occurred against the background of pathology of superficial bronchial epithelium with a decrease of HLA-DR and CD23 lymphocytes and increase of CD1c lymphocytes in lamina propria of bronchial mucosa of the liquidators. Verification of microorganisms characteristic of the upper respiratory tracts and atypical presence of Escherichia coli were found in the contents of the lower parts of broncho-pulmonary system of the liquidators. The obtained results testify to the activation of automicroflora and appearance of pathogenic microorganisms were caused by deterioration of specific and non-specific immune protection in liquidators with COLD.

[The ultrastructural characteristics of the bronchial mucosa in chronic inflammation in participants in the cleanup of the aftermath of the accident at the Chernobyl Atomic Electric Power Station]. / Ul'trastrukturnaia kharakteristika slizistoi obolochki bronkhov pri khronicheskom vospalenii u uchastnikov likvidatsii posledstvii avarii na ChAES.

Bronchial biopsies from persons exposed to radiation after the Chernobyl accident with clinically verified chronic bronchitis were studied by electron microscopy. The results demonstrate transformed alterative, compensatory-adaptive and inflammatory reactions in bronchial mucosa of contingent. Nevertheless, their integral significance does not alter the nosologic form, and some structural equivalents have dynamic expression.

[The morphogenesis of pathological processes in the gastric mucosa in chronic gastritis in servicemen who worked in the cleanup of the aftermath of the accident at the Chernobyl Atomic Electric Power Station]. / Morfohenez patolohichnykh protsesiv u slyzovii obolontsi shlunka pry khronichnomu hastryti u viis'kovosluzhbovtsiv--likvidatoriv naslidkiv avariï na ChAES.

Results are submitted of a complex structural analysis of 200 gastrobiopsies taken in those subjects with chronic gastritis who took part in the elimination of the aftermath of the Chernobyl accident, as well as in patients of a control nosologic group with no history of a radiation-factor exposure. The liquidators versus control patients demonstrated morphofunctional changes in gastric mucosa as potential manifestations of induced pathomorphosis of the condition. A number of propositions have been stated concerning features of morphogenesis of pathological processes in gastric mucosa under chronic gastritis in liquidators of the effects of the Chernobyl disaster.

[The morphological diagnosis of Helicobacter pylori in the gastric mucosa in chronic gastritis]. / Morfologicheskaia diagnostika Helicobacter pylori v slizistoi obolochke zheludka pri khronicheskom gastrite.

The importance is substantiated of morphologic verification of H. pylori infection in gastric mucosa in chronic gastritis. Based on the material of gastrobiopsies from 111 patients with chronic gastritis, 77 of whom took part in the elimination of the effects of the Chernobyl disaster, informative value was confirmed of different methods of structural analysis in respect of H. pylori. Arguments are advanced for optimization of therapeutic policy in H. pylori-associated gastritis.

[The dynamics of thyroid diseases in the inhabitants of Kiev and Kiev Province after the accident at the Chernobyl Atomic Electric Power Station]. / Dinamika zabolevanii shchitovidnoi zhelezy u zhitelei Kieva i Kievskoi oblasti posle avarii na ChAES.

Autoimmune affections of the thyroid gland were found to be on the increase as were Hashimoto's disease and follicular adenoma, as evidenced by a pathomorphic study in surgically removed thyroid glands of 12684 patients over 1984-1993. Rise in the frequency of malignant tumors was moderate. Increase in the incidence of papillary microcarcinoma against the background of another surgical pathology of the thyroid gland may be an unfavourable prognostic sign of further growth of morbidity of clinically manifest forms of carcinoma in Kiev and the Kiev Province.

[The morphofunctional instability of the lymphocyte membrane in patients with chronic kidney failure]. / Morfofunktsional'naia nestabil'nost' membrany limfotsitov u bol'nykh s khronicheskoi pochechnoi nedostatochnost'iu.

T-lymphocyte E-receptor activity, mobility of the surface and deep parts of lymphocytic membrane lipid bilayer and membrane transport function were studied in 47 patients with chronic renal failure (16 had a conservatively curable and 31 terminal stages). A rosette test, polarization of the fluorescent probes I-anilino-naphthaleno-8-sulfonate and pyrene, inclusion of 14C-uridine into immunocompetent cells were employed, respectively. The investigations demonstrate morphofunctional instability of the lymphocytic membranes as indicated by shifts in RFC E-receptor activity, in reduced microviscosity of the lipid bilayer and transport dysfunction. The disturbances progress with deterioration of renal function with their peak at the terminal stage of the disease. It is suggested that morphofunctional damage to the lymphocyte membranes cause, among other factors, lymphocytopenia and secondary immunodeficiency in chronic renal failure.

[The morphofunctional instability of the lymphocyte membranes in patients with chronic kidney failure]. / Morfofunktsional'naia nestabil'nost' membrany limfotsitov u bol'nykh s khronicheskoi pochechnoi nedostatochnost'iu.

A rosette test, fluorescent probing (1-aniline-naphthaline-8-sulfonate and pyrene) and 14C-uridine inclusion into immuno-competent cells were used to investigate T-lymphocyte membrane E-receptor activity, mobility of the surface and deep parts of lymphocytic membrane lipid bilayer, and membrane transport, respectively. A total of 16 patients with conservatively curable and 31 patients with a terminal stage of chronic renal failure (CRF) were examined. The lymphocytic membranes were found unstable: E-receptor activity of RFC changed, microviscosity of the surface and deep lipid bilayer diminished, the transport function got disturbed. These phenomena significantly progress with deterioration of renal function. It is evident that morphofunctional damage to lymphocytic membranes may be a reason of lymphocytopenia and secondary immunodeficiency in CRF patients.

[The structural bases of heart failure in ischemic heart disease]. / Strukturnye osnovy serdechnoi nedostatel'nosti pri ishemicheskoi bolezni serdtsa.

Regularities of structural changes and pathogenesis of pathological processes in the myocardium in intermediate form of ischemic heart disease indicates the necessity instituting adequate pathogenetic treatment and prophylaxis of hypertensive conditions, normalization of the coronary blood circulation, increase of the resistance of the myocardium to hypoxia, strengthening of reparative processes in the myocardium, activation of oxidation-reduction processes.

[Disordered lipid metabolism and the morphofunctional instability of the erythrocyte membranes in patients with terminal kidney failure]. / Narushenie obmena lipidov i morfofunktsional'naia nestabil'nost' membran éritrotsitov u bol'nykh s terminalnoi pochechnoi nedostatochnost'iu.

Fifty-two patients with terminal renal failure (TRF) placed on elective hemodialysis were examined for serum lipids and red blood cell membranes with the aid of chromatographic separation of lipids in thin-layer silica gel on Silufol plates followed by densitometry. Spectrocytophotometry was employed to study red blood cell distribution on the basis of the content of lipoproteins in TRF patients. Fluidity of the lipid bilayer of the red blood cell membrane was measured on Hitachi spectrofluorimeter according to the degree of eximerization of fluorescent pyrene. Dyslipidemia manifested itself as hyperlipidemia, hypertriglyceridemia, hypercholesterolemia and hyperphosphatidylcholinemia. The lipid profile of the red blood cell membranes was found to be deranged, which was evidenced by the reduced content of lipoproteins, total phospholipids, triglycerides, and cholesterol esters. In addition, there was a significant rise in the content of free cholesterol, lysolecithin and phosphatidyl ethanolamine. Impairment of lipid exchange between blood serum and the red blood cell membrane in TRF patients is under discussion. The changes in the lipid spectrum of the red blood cell membranes mirror their morphofunctional failure, supported by derangement of fluidity of the lipid bilayer of the red blood cell membrane. Both increase of viscosity of the lipid bilayer of the red blood cell membrane caused by a high level of cholesterol in the membrane and changes in the cholesterol/phospholipid ratio and reduction of the lipid bilayer viscosity related to the rise of the content of membrane lysolecithin in part of TRF patients were discovered. Hemodialysis influenced the lipid content of blood serum, producing no effect on the lipid spectrum of the red blood cells membrane.

[Morphogenetic characteristics of pneumonia in ischemic heart disease]. / Morfogeneticheskie osobennosti pnevmonii pri ishemicheskoi bolezni serdtsa.

It was established by histochemical and immunomorphological investigations that acute myocardial infarction results in an activation of the immune system of the body, immunomorphological changes in the lungs that plays a certain role in the pathogenesis of pneumonias in ischemic heart disease.

[Morphogenetic patterns of isolated infundibular stenosis of the pulmonary artery]. / Nekotorye morfogeneticheskie zakonomernosti izolirovannogo infundibulirnogo stenoza legochnoi arterii.

It was found that in isolated infundibular stenosis of the pulmonary artery a mass of muscle-fibrous tissue creates an obstacle to blood flow in the right ventricle. Morphogenetic regularities of compensatory and adaptive reactions in isolated infundibular stenosis are similar to those observed in hypertrophic cardiomyopathy. It may be suggested that abnormalities in the structure of the hypertrophied myocardium in isolated stenosis of the right ventricle infundibulum is a result of a fundamental error in the cardiac morphogenesis and not a reflection of increase of the degree of cardiac hypertrophy.

[Morphogenetic problems of dilated cardiomyopathy]. / Nekotorye voprosy morfogeneza dilatatsionnyi kardiomiopatii.

A comprehensive histochemical, histoenzymatic, morphometric and ultrastructural evaluation of 27 autopsy and 22 biopsy specimens of the right ventricular endomyocardium, aimed at the study of dilatation cardiomyopathy, revealed alteration, compensatory and adaptation response in the cardiac muscle. The processes were recorded light-optically and ultrastructurally. Discussed are the mechanisms of the disease morphogenesis and ways of relevant therapeutic correction.