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  • Review Article
  • Published:

Central nervous system injury-induced immune deficiency syndrome

Nature Reviews Neuroscience volume 6, pages 775–786 (2005)Cite this article

Key Points

  • Infections are a leading cause of death in patients suffering from acute CNS injury, such as stroke, traumatic brain injury or spinal cord injury. In affected patients infections impede neurological recovery and increase morbidity as well as mortality.

  • CNS injury induces a disturbance of the normally well balanced interplay between the immune system and the CNS.

  • Brain injury leads to a characteristic immunological phenotype, which is immunodepressant.

  • During systemic inflammation, either as a result of bacterial infection or injury, the CNS mounts a homeostatic, counter-regulatory anti-inflammatory response. However, when triggered by CNS injury, in the absence of systemic inflammation, this response may be detrimental because it shuts down defence mechanisms, rendering the affected organism susceptible to infection. Under these conditions, the immunodepression exerted by the brain is not balanced by general immunostimulation.

  • CNS injury suppresses cell-mediated immune responses via three major pathways of neuroimmunomodulation: the hypothalamo–pituitary–adrenal (HPA) axis, and the sympathetic and parasympathetic nervous systems.

  • We propose that 'neurogenic' mechanisms are involved in the induction of CNS injury-induced immunodepression (CIDS). Damage to sites in the nervous system that control neural–immune interactions (such as the hypothalamus) may lead to anti-inflammatory signals, without initial involvement of immune mechanisms.

  • CIDS is an important, independent contributor to the negative outcomes of patients with brain injury.

  • Recognizing and understanding CIDS could lead to novel treatment strategies to improve outcome in patients with CNS injury.

Abstract

Infections are a leading cause of morbidity and mortality in patients with acute CNS injury. It has recently become clear that CNS injury significantly increases susceptibility to infection by brain-specific mechanisms: CNS injury induces a disturbance of the normally well balanced interplay between the immune system and the CNS. As a result, CNS injury leads to secondary immunodeficiency — CNS injury-induced immunodepression (CIDS) — and infection. CIDS might serve as a model for the study of the mechanisms and mediators of brain control over immunity. More importantly, understanding CIDS will allow us to work on developing effective therapeutic strategies, with which the outcome after CNS damage by a host of diseases could be improved by eliminating a major determinant of poor recovery.

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Figure 1: The nervous and immune systems are engaged in bidirectional communication.
Figure 2: Interactions between the central nervous system and the immune system.
Figure 3: Most types of CNS injury can lead to direct damage to sympathetic CNS structures involved in vegetative neuroimmunomodulation.
Figure 4: Scheme summarizing the pathophysiological events that lead from CNS injury to infection and worsening of patient outcome.

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Acknowledgements

The authors' work is supported by the Hermann and Lilly Schilling Foundation, the Wings for Life Spinal Cord Research Foundation, and the Deutsche Forschungsgemeinschaft.

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  1. Jan M. Schwab

    Present address: The Brigham and Women's Hospital, Center for Experimental Therapeutics, Harvard Medical School, 75 Francis Street, Thorn 724, Boston, 02115, Massachusetts, USA

Authors and Affiliations

  1. Departments of Medical Immunology, Charité, Humboldt University, Berlin, 10098, Germany

    Christian Meisel

  2. Departments of Neurology and Experimental Neurology, Charité, Humboldt University, Berlin, 10098, Germany

    Konstantin Prass, Andreas Meisel & Ulrich Dirnagl

  3. Institute of Brain Research, Eberhard-Karls University Tübingen, Calwerstr. 3, Tübingen, 72076, Germany

    Jan M. Schwab

  4. CNRS UMR 7102, Université Pierre et Marie Curie (VI), Equipe Developpement Neuronal, Batiment B, Case 12, 9 Quai Saint Bernard, Paris, 75005, France

    Jan M. Schwab

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Correspondence to Jan M. Schwab.

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Competing interests

A patent application on preventive anti-infective and immunomodulatory therapy in stroke has been filed by A. M., C. M., K. P. and U. D. to the European Patent Office. Patent owner: Charité Universitätsmedizin Berlin.

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DATABASES

Entrez Gene

ACTH

CGRP

CRF

IFNγ

IL-1β

IL-6

NPY

TNFα

VIP

FURTHER INFORMATION

Department of Experimental Neurology, Charité, Berlin

Glossary

INNATE AND ADAPTIVE IMMUNITY

The early phases of the host response to a pathogen depend on innate resistance mechanisms. The activation of innate effector mechanisms induces the clonal expansion of antigen-specific lymphocytes and initiates adaptive immune responses, including the development of immunological memory.

STROKE

There are two main types of stroke: ischaemic (caused by blockage in an artery that supplies blood to the brain) and haemorrhagic (caused by the bleeding of ruptured blood vessels in the brain).

NOSOCOMIAL

A disease acquired in hospital.

HYPOXAEMIA

Describes critically decreased arterial oxygen levels.

SYSTEMIC INFLAMMATORY RESPONSE SYNDROME

(SIRS). This describes the host response to a critical illness of either infectious or noninfectious aetiology. The response is mediated by a cascade of pro-inflammatory mediators, such as inflammatory cytokines (for example, TNFα), activated complement factors and lipid mediators.

HUMORAL

Derived from the blood.

ENDOTOXINS

Inflammatory bacterial cell wall products that can cause sepsis.

TYPE 1 T-HELPER T CELLS

(Th1). T-helper cells can be divided on the basis of their cytokine expression pattern. Th1 cells produce mostly IFNγ and mediate delayed-type hypersensitivity and protection against intracellular pathogens.

TYPE 2 T-HELPER T CELLS

(Th2). Th2 cells produce mainly IL-4 and IL-5, and have been implicated in humoral and allergic immune responses.

COMPENSATORY ANTI-INFLAMMATORY RESPONSE SYNDROME

(CARS). The systemic inflammatory response induces, and is then balanced by, counter-regulatory processes, known as CARS. This includes the release of anti-inflammatory molecules (for example, IL-10) and activation of neuroendocrine pathways (for example, the HPA axis).

NEUROGENIC

Caused by a primarily neuronal mechanism through either blockade or stimulation of trans-synaptic nerve conduction.

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Meisel, C., Schwab, J., Prass, K. et al. Central nervous system injury-induced immune deficiency syndrome. Nat Rev Neurosci 6, 775–786 (2005). https://doi.org/10.1038/nrn1765

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