Asthma and allergy in teenagers and young adults, risk-factors and T-cell regulation

Asthma is one of the most common chronic diseases among teenagers and young adults. The prevalence of asthma among young adults in Sweden is approximately 7-10%. Despite this, only a limited number of studies have focused on asthma, allergy and allergic inflammation in this age group. The aims of this thesis are to study the consequences of asthma and allergy in teenagers and young adults, incidence and riskfactors for death due to asthma, and deterioration in asthma prior and following transfer from pediatric to adult health care. As allergic inflammation is involved in a majority of asthma patients in this age-group we have further investigated a T cell mediated inflammatory mechanism with possible implications in monitoring and modulating autoimmune and allergic diseases.

Paper I: During the 1994-2003 period 37 deaths due to asthma were identified. The incidence of asthma in 1-34 year-olds decreased during the period from 1.54 to 0.53 per million. Common risk-factors were under-treatment, poor adherence to prescribed treatment and adverse psychosocial situation. An alarming finding was that 11/37 deaths was probably caused by food allergy and 8/37 were associated with exposure to pet dander.

Paper II: In a 5-year prospective follow-up study to identify risk factors for deterioration of asthma following transfer from pediatric to adult health care 150 teenagers with asthma were enrolled. Skin prick test at entrance revealed that 89% were sensitized towards at least one of tested allergens. A minority performed with impaired lung function without deterioration during the five-year follow up, while bronchial hyper responsiveness (BHR) was present in 71% of the subjects at entrance and among 59% at follow-up. Risk for persistence of BHR after five years was elevated by poor adherence and attenuated by regular physical activity. Working capacity decreased significantly during the study period without any correlation to risk factors examined.

Paper III: Interactions between the low-density lipoprotein receptor-related protein 1(LRP1) and thrombospondin-1 (TSP-1) is necessarily for T cell motility and that the motogenic LRP/TSP-1 mechanism antagonizes adhesion to ICAM-1 and fibronectin as well as TCR induced proliferative responses. This cascade mediates regulatory effects of IL-2 and IL-4. In addition expression of TSP-1, with known ability to protect against inflammation, was increased by IL-2.

Paper IV: T cell activation induces arrest of T cell motility through down-regulation of LRP1 synthesis a concomitant up-regulation of TSP-1 synthesis providing a mechanism for enhancement of adhesion of T cells to APC´s stimulating proliferative responses. Despite this arrest of motility, co-ligation with CD28 maintains a basal motility level by enhancing transport of LRP1 to the cell surface.

Paper V: Patients with allergy and psoriasis showed impaired T cell motility and decreased TSP-1 expression compared to healthy controls. IL-2 was shown to up-regulate the impaired motility in patient to the same level as in controls indicating a reversible state probably excluding a constitutional defect.

List of scientific papers

I. Bergström SE, Boman G, Eriksson L, Formgren H, Foucard T, Hörte LG, Janson C, Spetz-Nyström U, Hedlin G. Asthma mortality among Swedish children and young adults, a 10-year study. Respir Med. 2008 Sep; 102(9):1335-41.
https://doi.org/10.1016/j.rmed.2008.03.020

II. Bergström SE, Sundell K, Hedlin G. Adolescents with asthma: Consequences of transition from paediatric to adult healthcare. Respir Med. 2010 Feb; 104(2):180-7.
https://doi.org/10.1016/j.rmed.2009.09.021

III. Bergström SE, Bergdahl E, Sundqvist KG. A cytokine-controlled mechanism for integrated regulation of lymphocyte motility, adhesion and activation. Immunology. Immunology. 2013; 140:441-55.
https://doi.org/10.1111/imm.12154

IV. Bergström SE, Uzunel M, Talme T, Bergdahl E, Sundqvist KG. The TCR Collaborates with CD28 to regulate T cell Motility and an Anti-Inflammatory Response through Endogenous Thrombospondin-1 and Low Density Lipoprotein Receptor-Related Protein 1. [Submitted]

V. Bergström SE, Talme T, Skedinger M, Sundell-Bergström K, Bergdahl E, Sundqvist KG. Dysfunctional Regulation of T cell Motility in Patients with Allergy and Autoimmunity. [Manuscript]