The Wonder Years: What Can Primary School Children Teach Us About Immunity to Mycobacterium tuberculosis?

Abstract

In high burden settings, the risk of infection with Mycobacterium tuberculosis increases throughout childhood due to cumulative exposure. However, the risk of progressing from tuberculosis (TB) infection to disease varies by age. Young children (<5 years) have high risk of disease progression following infection. The risk falls in primary school children (5 to <10 years), but rises again during puberty. TB disease phenotype also varies by age: generally, young children have intrathoracic lymph node disease or disseminated disease, while adolescents (10 to <20 years) have adult-type pulmonary disease. TB risk also exhibits a gender difference: compared to adolescent boys, adolescent girls have an earlier rise in disease progression risk and higher TB incidence until early adulthood. Understanding why primary school children, during what we term the "Wonder Years," have low TB risk has implications for vaccine development, therapeutic interventions, and diagnostics. To understand why this group is at low risk, we need a better comprehension of why younger children and adolescents have higher risks, and why risk varies by gender. Immunological response to M. tuberculosis is central to these issues. Host response at key stages in the immunopathological interaction with M. tuberculosis influences risk and disease phenotype. Cell numbers and function change dramatically with age and sexual maturation. Young children have poorly functioning innate cells and a Th2 skew. During the "Wonder Years," there is a lymphocyte predominance and a Th1 skew. During puberty, neutrophils become more central to host response, and CD4+ T cells increase in number. Sex hormones (dehydroepiandrosterone, adiponectin, leptin, oestradiol, progesterone, and testosterone) profoundly affect immunity. Compared to girls, boys have a stronger Th1 profile and increased numbers of CD8+ T cells and NK cells. Girls are more Th2-skewed and elicit more enhanced inflammatory responses. Non-immunological factors (including exposure intensity, behavior, and co-infections) may impact disease. However, given the consistent patterns seen across time and geography, these factors likely are less central. Strategies to protect children and adolescents from TB may need to differ by age and sex. Further work is required to better understand the contribution of age and sex to M. tuberculosis immunity.

Keywords: Mycobacterium tuberculosis; adolescence; children; immunity; infection; protection; tuberculosis; vaccination.

Figure 1

Conceptual framework to demonstrate the pattern of change in tuberculosis incidence with age. This represents a composite of risk of infection and risk of subsequent disease progression. The presentation of disease is demonstrated by a representative X-ray in a box colored according to the disease phenotype legend.

Figure 2

The Immunopathology of tuberculosis, demonstrating the host response at key stages in the host pathogen interaction and how age influences risk and disease phenotype. Transmission from an infectious case can lead to infection, which in turn encounters the innate immune response, the adaptive immune response, and, if not controlled, progresses to early and then late stage disease. The organism can be eliminated by either the innate or adaptive immune response. Young children are at increased risk of pathological lymph node enlargement and disseminated disease, whereas adolescents/adults are at increased risk of immunopathology. Pre-pubertal children are the most likely to contain M. tuberculosis.

Figure 3

Change in tuberculosis risk throughout life stages compared to fluctuations in hormone levels, circulating cell populations (“Cells”), immune functions (“Immunity”), co-infections (“Infections”), and social interactions and behaviors (“Behavior”). TB risk is indicated by the gray shading with peaks of risk indicated underneath various life course stages. Images represent infections: mosquito, malaria; worm, helminths; virus, EBV, CMV, influenza; and behaviors: infant exposures to adult TB, children playing outdoors, smoking, drinking, sexual activity, pregnancy, Diabetes Mellites and old age. B, B cells; DC, dendritic cells; IFN, interferon; MN, monocytes; N, neutrophils; NK, natural killer cells; T, T lymphocytes; Th, T helper; Treg, regulatory T cells; WBC, white blood cells.

Figure 4

Immunological differences observed between males and females, post-puberty. TB disease risk increases as the immune response more heavily favors either Th2 or Th1 skewing, with a more balanced Th1/Th2 response having the lowest risk of disease progression. In general, males are Th1 skews and females Th2 skewed, although females have a higher inflammatory response to an exogenous stimulus, partly mediated by variable X-inactivation and the presence of estrogen response elements in many immune response genes, leading to higher responses once activated. BCR, B cell receptor; Ig, immunoglobulin; IL, interleukin; NK, natural killer; iNOS, inducible nitric oxide synthase; Th, T helper; TGFß, transforming growth factor-beta; TNF, tumor necrosis factor; #, number.