Motherechild immunological interactions in early life affect long-term humoral autoreactivity to heat shock protein 60 at age 18 years Gabriel D. Victora a,b , Angelina M.B. Bilate a,b , Adalberto Socorro-Silva a,b,c , Cristina Caldas a,b , Rosangela C. Lima d , Jorge Kalil a,b,c , Vero ˆnica Coelho a,b,c, * , Cesar G. Victora d a Laboratory of Immunology, Heart Institute (InCor), University of S~ ao Paulo Medical School, Brazil b Institute for Investigation in Immunology-Millennium Institute, S~ ao Paulo, Brazil c Division of Clinical Immunology and Allergy, University of S~ ao Paulo Medical School, S~ ao Paulo, Brazil d Post-graduate Program in Epidemiology, Federal University of Pelotas, Pelotas, Brazil Received 22 July 2006; revised 31 January 2007; accepted 6 February 2007 Abstract The presence of anti-heat shock protein 60 (Hsp60) antibodies in healthy individuals and the association of these antibodies with diseases such as arthritis and atherosclerosis are well documented. However, there is limited population-level data on interindividual variation in anti- Hsp60 levels. We investigated the influence of early-life factors on IgG reactivity to human Hsp60 at age 18 years. A population-based prospec- tive birth cohort study included 5914 births in the city of Pelotas, Brazil, in 1982. Early-life exposures were documented during home visits in childhood. In 2000, 79% of all males in the cohort were traced. Sera from a systematic 20% sample (411 subjects) were analyzed. Anti-Hsp60 total IgG reactivity was determined by ELISA. Data were analyzed using analysis of variance and generalized linear models. Anti-Hsp60 re- activity was lognormally distributed and showed a significant direct correlation with low birthweight ( p ¼ 0.039) and total duration of breast- feeding ( p ¼ 0.018), of which only the latter remained significant after adjustment for potential confounders. Reactivity was not associated with asthma, pneumonia, diarrhea, or early-life malnutrition. Motherechild immunological interactions, rather than infection/disease factors seem to be associated with reactivity to Hsp60 later in life. This is in agreement with the hypothesis that maternal antibodies influence future antibody profile. Ó 2007 Elsevier Ltd. All rights reserved. Keywords: Autoantibodies; Birthweight; Breastfeeding; Cohort studies; Heat shock protein 60 1. Introduction Heat shock proteins (HSPs) are a family of phylogenetically conserved proteins present in all cells of all living organisms, performing various intracellular and systemic homeostatic functions. They are so named because of their increased expression in stress situations, including heat shock, oxidative stress, ultraviolet radiation, and viral infection [1]. In addition to their role in intracellular maintenance, heat shock proteins also seem to interact extensively with the immune system, through both the innate and adaptive branches. This is espe- cially the case for the 60 kDa member of this family, heat shock protein 60 (Hsp60), which has been reported to be involved in both triggering and helping downmodulate immune responses [2]. Hsp60 is also part of the ‘immunological homunculus,’ postulated by Cohen and Young [3], which consists of a limited set of self-antigens preferentially recognized by a regulatory network of autoreactive T and B cells. Naturally occurring autoantibodies to human Hsp60 are found in most, if not all individuals [4], and seem to remain at stable levels for long periods of time [5]. This is compatible with the concept that antibody autoreactivity may contribute to the maintenance of homeostasis [6]. On the other hand, * Corresponding author. Laborato ´rio de Imunologia do InCor, Av. Dr. Eneas de Carvalho Aguiar, 44, bloco-2, 9  andar, S~ ao Paulo, SP 05340-000, Brazil. Tel.: þ55 11 3069 5905; fax: þ55 11 3069 5953. E-mail address: vecoelho@usp.br (V. Coelho). 0896-8411/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.jaut.2007.02.018 Journal of Autoimmunity 29 (2007) 38e43 www.elsevier.com/locate/jautimm