Review article
Histologic and molecular assessment of human thymus

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Abstract

Most work describing the histopathology of normal human thymus has focused on pediatric thymus because of tissue availability and high thymopoietic activity. However, pathologic examination of the thymus can provide information about immune status that is relevant to the clinical care of patients of all ages. Understanding age-related changes in the relative abundance and composition of anatomic compartments within the thymus is critical for evaluation of the thymus in normal adults and patients with diseases that affect the thymus. The purpose of this review is to acquaint diagnostic pathologists with some of the newer histologic, flow cytometric, and molecular techniques for assessment of non-neoplastic thymus. Diagnostic criteria are presented for assessment of thymic function and for determining the mechanisms underlying thymic hyperplasia. Accurate assessment of thymic function is critical for the diagnosis and treatment of patients with complete DiGeorge syndrome and can complement the clinical care of patients with a variety of disorders that affect the immune system.

Section snippets

Age-Related changes in thymus histology and function

The thymus has traditionally has been considered to be composed of a cortex and a medulla, which contain developing thymocytes within a network of thymic epithelial and stromal cells. Hassall bodies composed of swirls of terminally differentiated thymic epithelial cells9, 10, 11, 12 are present in the medulla and are a universally recognized histologic indicator of the thymus. Because they both contain thymic epithelial cells, the cortex and medulla can also be referred to together as the

Histologic and flow cytometric assessment of thymic function

A large number of research studies in both animals and humans have determined the phenotype of immature and mature thymocytes and peripheral lymphocytes and have established appropriate cell surface markers that distinguish between them. The most immature thymocytes (“triple negative thymocytes”) do not express CD3, CD4, or CD8, although they typically express other lymphocyte markers such as CD45 and CD7. As these thymocytes begin to undergo T-cell receptor gene rearrangement, they acquire

Molecular analysis of thymic function

T-cell receptor gene rearrangement is a defining event of T-cell development within the thymus. Molecular techniques for assessing thymic function can be divided into two types: those that analyze thymic tissue directly for the presence of ongoing T-cell receptor gene rearrangement and those that analyze peripheral T cells for evidence of prior T-cell rearrangement within the thymus.

To create T-cell receptors with unique specificities, concerted DNA breakage and repair occurs at specific

Thymic hyperplasia

The non-malignant thymic enlargement that has been classically termed “thymic hyperplasia” may occur because of two distinct mechanisms, with different implications for patient treatment and prognosis. Marked thymic enlargement may be seen in settings of thymic reconstitution after chemotherapy33 or after institution of highly active antiretroviral therapy in HIV-infected patients.27, 28, 29 True thymic hyperplasia with active thymopoiesis is characterized by expansion of the thymic epithelial

Evaluation of thymus from pediatric patients with suspected immunodeficiency

The thymus from patients with severe combined immunodeficiency is typically markedly hypoplastic (<3 g; normal 12 ± 5 g for 12-month-old male infant).37, 38 Severe combined immunodeficiency thymus consists of compact lobules of tightly opposed thymic epithelial cells surrounded by a small amount of adipose tissue (Fig 9A). Concentrically arranged thymic epithelial cells (epithelial “pseudo-rosettes”) may be present focally (Fig 9B). CD1a+ small lymphocytes (ie, immature thymocytes) are absent,

Evaluation of thymic reconstitution

Most studies of patients undergoing therapy for congenital immunodeficiencies, HIV infection, or cancer have used radiographic determination of thymus size and/or the TREC assay combined with flow cytometric identification of CD3+CD45RA+ CD62Lhigh (naive) T cells to determine thymic reconstitution status.27, 30, 33 The immunoscope assay has also been used to monitor normalization of the T-cell receptor repertoire and to identify patients who have been successfully immunoreconstituted and thus

Summary

The thymus is absolutely required to initially establish a functional T-cell repertoire in humans, but begins to undergo age-related decreases in activity, beginning in early childhood. Histologic and molecular methods have been developed to assess thymic activity as a function of age in normal humans and in disease states that affect the thymus. Although thymic volume and weight remain relatively constant, the portion of the thymus containing thymic epithelium and participating in production

Acknowledgements

The author would like to thank Steven Conlon for assistance with figure preparation and Drs Barton F. Haynes and John Whitesides for providing Figure 4. The data used to prepare Figure 6B were provided by Drs Dhavel D. Patel, Rebecca H. Buckley, Gregory D. Sempowski, and Barton F. Haynes. Dr M. Louise Markert provided the immunostained sections used to prepare Figure 11.

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