Elsevier

Human Pathology

Volume 38, Issue 8, August 2007, Pages 1239-1247
Human Pathology

Original contribution
Lung involvement in childhood measles: severe immune dysfunction revealed by quantitative immunohistochemistry

https://doi.org/10.1016/j.humpath.2007.01.015Get rights and content

Summary

Measles, accounting for nearly 1 million deaths each year, presents intense involvement of lymphoid organs and the lungs. The immune response in situ in the lungs was determined in blocks recovered from 42 necropsies of children who died from measles determined by immune cell phenotype (CD4, CD8, CD20, CD45RO, CD68, natural killer [NK], and antigen S-100 B [S100]) and cytokine production (interferon, tumor necrosis factor, interleukin [IL]-1, IL-2, IL-4, IL-10, and IL-12). Compared with the lungs of age-paired controls, patients with measles presented severe depletion of CD4+, CD20+, CD68+, NK+, and S100+ cells in alveolus- and bronchus-associated lymphoid tissue without depletion of CD8+ cells. Most of these features were similar in both forms of measles lung involvement, Hecht giant cell, or interstitial pneumonia, but S100+ cells were depleted in bronchus-associated lymphoid tissue from patients with Hecht pneumonia, which also occurs more frequently in malnourished children. IL-10– and IL-12–producing cells were depleted in patients with measles, whereas IL-1–, interferon-, and IL-4–producing cells were more frequently seen in the alveolus of patients with measles compared with controls. Quantitative in situ immune cell phenotype and function in the lung in measles demonstrated severe immune dysfunction, with loss of key cells, such as dendritic, CD4+, and NK+ cells, and deficient cytokine production, which allows for a better comprehension of local reactions in this process.

Introduction

Measles, or rubeola, is the oldest virus-induced disease known to cause serious damage to immune function [1]. Despite the efficacy of its vaccine, measles continues to cause approximately 770,000 deaths around the world each year, especially in third world countries and with isolated outbreaks in developed nations [2]. Measles is accompanied by high morbidity and mortality, mainly in malnourished children [1] because of lethal complications such as secondary infections, especially pneumonia and upper respiratory tract involvement, due to either direct measles virus (MV) effect or its indirect disabling effects on the immune system [3].

The immune system is affected by MV in both innate and adaptive immune responses. MV attacks natural killer (NK) cells leading to the down-regulation of their lytic activity [4]. Heat shock proteins are also subverted by MV to induce viral product transcription, which, in turn, induces more heat shock proteins to be synthesized, causing a positive feedback loop where the virus multiplies and raises its numbers inside the cell [5].

Infection of dendritic cells leads to fusion of these cells with macrophages and with each other, forming giant cells that are unable to exert antigen-presenting function and constitute an ideal place for virus multiplication [6]. Infection of dendritic cells also causes apoptosis, which diminishes their numbers in the lung tissue, affecting the transition from the innate phase to the adaptive phase of the immune response [7].

MV damages the adaptive immune responses, but interestingly, the virus infection induces a life-long protective immunity, although the acute disease causes severe impairment of immune responses to other microorganisms [4]. During this acute phase, Th1 type of immune response occurs with a drastic antiviral effect, clearing the virus, as seen in the skin by cytotoxic CD8+ cell infiltration [8]. Interferon γ (IFNγ) is present in the acute phase of measles in the prerash period, followed by interleukin (IL)-2, characteristic Th1 cytokines. During and after the exanthema, the immune system turns its response to the Th2 profile. IL-4 begins to predominate and acts as a Th2 immunity trigger [7]. Specific IgG subtype production changes from IgG1 to IgG4, as well as high IgE plasma levels [9].

Measles, or rubeola, presents 2 main lung involvements. The classic giant cell pneumonia, or Hecht pneumonia, is more severe and frequently associated with respiratory failure and death [1]. Unfortunately, patients often die with histological lung involvement that is indistinct from interstitial pneumonia, except for detection by additional diagnostic immunohistochemistry or electron microscopy for viral detection. The pathogenic mechanisms of lung involvement are not well understood, but they are attributed to both direct MV action and indirect effect causing generalized immune disruption [4]. The lungs are directly exposed to the external environment, being protected by cilia, mucus, alveolar macrophages, and a powerful bronchus-associated lymphoid tissue (BALT) [10]. This lymphoid lung tissue has been reported to mature and change with age, but few, if any, studies exist on pulmonary infections [10], [11].

In the present study, we investigate the in situ immune response caused by MV in the lungs from children who died due to measles or rubeola, grouped according to main histological lung involvement. We quantify the numbers of immune cells and their activation evidenced by cytokine production, by quantitative immunohistochemistry in areas of lung structures such as the alveolus, septum, and BALT, and by the response to viral infection.

Section snippets

Cases and controls

The necropsies from patients diagnosed as having measles or rubeola were recovered from the files of Instituto Emilio Ribas in São Paulo (Brazil) and Hospital Infantil Nossa Senhora da Glória in Vitória (Brazil). We excluded cases with concomitant diagnosis of bacterial pneumonia and patients more than 20 years of age. We recovered the paraffin blocks and rechecked lung histology, excluding cases that had evidence of tissue autolysis, inappropriate fixation with artifacts, or typical bacterial

Results

Demographic and histological parameters of our sample are described in Table 1, with comparison to an age-matched control group from children with left ventricle congenital disease without significant lung disease. Clear histological parameters of measles with lung involvement allow classification of Hecht pneumonia (14/42) or interstitial pneumonia (28/42) based on giant cell presence and pneumocyte I necrosis. Most patients classified with Hecht pneumonia were considered malnourished at

Discussion

We observed that the main subtypes of cells detected in situ and involved in measles lung immune dysfunction are T helper lymphocytes (CD4+), B lymphocytes (CD20+), and pulmonary dendritic cells (S100+), which were depleted in all pulmonary tissues studied such as in alveoli and BALT. Both measles forms of pneumonia, Hecht giant cell and interstitial pneumonia, showed this pattern of involvement of immune cells in the lung, confirmed by viral etiology performed by immunohistochemistry and

Acknowledgments

The authors acknowledge Dr Carlos Musso of the Hospital Infantil Nossa Senhora da Glória-Vitória ES, Brazil, and the Instituto Emílio Ribas-São Paulo for providing paraffin blocks of the lungs from measles-infected necropsies; and Dr Vera Demarchi Aiello of the Heart Institute (InCor), University of São Paulo Medical School, Brazil, for providing blocks of control cases to the present work. The authors thank James Hesson for providing the English revision of this article.

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  • Cited by (0)

    This work was supported by Conselho Nacional de Pesquisas and Instituto dos Laboratórios de Investigação Médica do Hospital das Clínicas da Faculdade de Medicina da USP.

    1

    The following authors take the responsibility for the integrity of the work.

    2

    The following authors are responsible for morphometry and immunohistochemistry.

    3

    The following author collaborated with lung histopathology analysis.

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