Autoreactive T and B cell responses to myelin antigens after diagnostic sural nerve biopsy

doi:10.1016/0022-510X(93)90165-U

Journal of the Neurological Sciences

Volume 117, Issues 1–2, July 1993, Pages 130-139

https://doi.org/10.1016/0022-510X(93)90165-U Get rights and content

Abstract

To study whether nervous tissue trauma provokes myelin antigen autoreactive T and B cell responses in humans we examined consecutive blood samples from 7 patients with polyneuropathy undergoing diagnostic sural nerve biopsy and 8 control patients undergoing other types of minor surgery. The antigen-specific T cells were assessed by enumerating cells secreting interferongamma (IFN-γ) in response to the myelin components P₀, P₂, myelin basic protein (MBP) and myelin associated glycoprotein (MAG), and to 4 selected MBP peptides. B cell mediated immunity was assessed by counting numbers of cells secreting antibodies directed against the myelin proteins. On day 7 after biopsy, there were 3-10-fold increased numbers of T and B cells reactive with P₀, P₂, MBP and MAG in blood of polyneuropathy patients compared to controls, while levels of cells recognizing purified protein derivate or responding to phytohemagglutinin (PHA) did not differ significantly. Comparison of prebiopsy levels on day 0 with post-biopsy levels on day 7 in the polyneuropathy patients revealed a significant increase in T cells recognizing P₀, P₂ and MAG, and in B cells secreting IgG antibodies against P₀ and P₂. On day 14 after nerve biopsy these differences were no longer seen. We suggest that in patients with polyneuropathy, sural nerve biopsy with the ensuing wallerian degeneration and myelin breakdown causes transiently increased levels of circulating myelin autoreactive T and B cells. It remains to be determined if this has a physiological role in nerve trauma responses and/or affects the clinicopathological course of the peripheral neuropathy.

References (46)

G. Andersson et al.
Monoclonal antibody two-site ELISA for human IFN-γ
Adaption for determinations in human serum or plasma
J. Immunol. Methods
(1989)
J. Correale et al.
Sulfosalazine treatment of experimental allergic encephalomyelitis in Lewis rats: disease relapse and increase of autoreactive T cells
J. Neuroimmunol.
(1991)
M. Kadlubowski et al.
Experimental allergic neuritis in the Lewis rat: characterization of the activity of peripheral myelin and its major basic protein P₂
Brain Res.
(1980)
Y.D. Karkhanis et al.
Allergic encephalomyelitis isolation of an encephalitogenic peptide active in the monkey
J. Biol. Chem.
(1975)
H. Link et al.
Persistent anti-myelin basic protein IgG antibody response in multiple sclerosis cerebrospinal fluid
J. Neuroimmunol.
(1990)
P.A. Milner et al.
P0 myelin protein produces experimental allergic neuritis in Lewis rats
J. Neurol. Sci.
(1987)
M.I. Mustafa et al.
T cell immunity and interferon-γ secretion during experimental allergic encephalomyelitis in Lewis rats
J. Neuroimmunol.
(1991)
R. Quarles et al.
Purification and partial characterization of the myelin associated glycoprotein from adult rat brain
Biochim. Biophys. Acta
(1983)
K. Sakai et al.
Characterization of a major encephalitogenic T-cell epitope in SJL/J mice with synthetic oligopeptides myelin basic protein
J. Neuroimmunol.
(1988)
D.O. Adams et al.
Molecular transductional mechanisms by which IFN-γ and other signals regulate macrophage development
Immunol. Rev.
(1987)

A.K. Asbury et al.

Technique of sural nerve biopsy

A. Ben-Nun et al.

The rapid isolation of clonable antigen specific lines capable of mediating autoimmune encephalomyelitis

Eur. J. Immunol.

(1981)

A. Ben-Nun et al.

Genetic control of autoimmune encephalomyelitis and recognition of the critical nonapeptide moiety of myelin basic protein in guinea pigs are exerted through interaction of lymphocyte and macropahges

Eur. J. Immunol.

(1981)

C. Czerkinsky et al.

Detection of single antibody-secreting cells generated after in vitro antigen-induced stimulation of human peripheral blood lymphocytes

Scand. J. Immunol.

(1984)

G.E. Deibler et al.

Large scale preparation of myelin basic protein from central nervous tissue of several mammalian species

Prep. Biochem.

(1972)

A.M. Duijvestijn et al.

Interferon-gamma regulates an antigen specific for endothelial cells involved in lymphocyte traffic

H.P. Hartung et al.

The role of interferon-gamma in the pathogenesis of experimental autoimmune disease of the peripheral nervous system

Ann. Neurol.

(1990)

F. Heinzel et al.

Reciprocal expression of interferon γ or interleukin 4 during the resolution of progression of murine leishmaniasis

Evidence for expansion of distinct helper T cells

J. Exp. Med.

(1989)

L. Jansson et al.

Chronic experimental autoimmune encephalomyelitis induced by the 89–101 myelin basic protein peptide in B10RIII (H-2^r) mice

Eur. J. Immunol.

(1991)

L. Kabilan et al.

Detection of intracellular expression and secretion of interferon-γ at the single cell level after activation of human T cells with tetanus toxoid in vitro

Eur. J. Immunol.

(1990)

L.S. Kaplow

Substitute for benzidine in myeloperoxidase stains

Am. J. Clin. Pathol.

(1974)

W.J. Karpus et al.

CD4⁺ suppressor

cells inhibit the function of effector cells of experimental autoimmune encephalomyelitis through a mechanism involving transforming growth factor-β

J. Immunol.

(1991)

C. Linington et al.

A permanent rat T cell line that mediates experimental allergic neuritis in the Lewis rat in vivo

J. Immunol.

(1984)

Cited by (41)

Lymphocytes and autoimmunity after spinal cord injury
2014, Experimental Neurology
Citation Excerpt :
There is evidence from both human and animal studies demonstrating that trauma activates an endogenous repertoire of CNS-reactive lymphocytes. The frequency of T lymphocytes reactive to myelin proteins (e.g., myelin basic protein (MBP)) is increased in the serum of SCI patients (Kil et al., 1999; Olsson et al., 1993; Wucherpfennig et al., 1994; Zajarias-Fainsod et al., 2012) and SCI patients have chronically elevated titers of serum autoantibodies (Davies et al., 2007; Hayes et al., 2002; Mizrachi et al., 1983; Zajarias-Fainsod et al., 2012). Collectively, these data indicate the functional activation of autoreactive T- and B-cells, a phenomenon that we previously designated as trauma-induced autoimmunity, or TIA (Popovich and Jones, 2003; Popovich et al., 1996).
Over the past 15 years an immense amount of data has accumulated regarding the infiltration and activation of lymphocytes in the traumatized spinal cord. Although the impact of the intraspinal accumulation of lymphocytes is still unclear, modulation of the adaptive immune response via active and passive vaccination is being evaluated for its preclinical efficacy in improving the outcome for spinal-injured individuals. The complexity of the interaction between the nervous and the immune systems is highlighted in the contradictions that appear in response to these modulations. Current evidence regarding augmentation and inhibition of the adaptive immune response to spinal cord injury is reviewed with an aim toward reconciling conflicting data and providing consensus issues that may be exploited in future therapies. Opportunities such an approach may provide are highlighted as well as the obstacles that must be overcome before such approaches can be translated into clinical trials.
Both MHC and non-MHC genes regulate inflammation and T-cell response after traumatic brain injury
2011, Brain, Behavior, and Immunity
Citation Excerpt :
DA rats displayed fewer T cells in relation to MHC II+ cells, suggesting additional effects by non-MHC genes. Encephalitogenic responses have been described after experimental nerve injury and MBP autoreactive T-cell responses have been described also in the human (Olsson et al., 1992, 1993). We were here unable to detect any overt lymphocyte infiltrates on histological examination and stimulation of deep cervical lymph node cells did not result in any immunogenic response on recall with MBP63-88.
Genetic regulation of autoimmune neuroinflammation is a well known phenomenon, but genetic influences on inflammation following traumatic nerve injuries have received little attention. In this study we examined the inflammatory response in a rat traumatic brain injury (TBI) model, with a particular focus on major histocompatibility class II (MHC II) presentation, in two inbred rat strains that have been extensively characterized in experimental autoimmune encephalomyelitis (EAE); DA and PVG. In addition, MHC and Vra4 congenic strains on these backgrounds were studied to give information on MHC and non-MHC gene contribution. Thus, allelic differences in Vra4, harboring the Ciita gene, was found to regulate expression of the invariant chain at the mRNA level, with a much smaller effect exerted by the MHC locus itself. Notably, however, at the protein level the MHC congenic PVG-RT1^av1 strain displayed much stronger MHCII⁺ presentation, as shown both by immunolabeling and flow cytometry, than the PVG strain, dwarfing the effect of Ciita. The PVG-RT1^av1 strain had significantly more T-cell influx than both DA and PVG, suggesting regulation both by MHC and non-MHC genes. Finally, in terms of outcome, the EAE susceptible DA strain displayed a significantly smaller resulting lesion volume than the resistant PVG-RT1^av1 strain. These results provide additional support for a role of adaptive immune response after neurotrauma and demonstrate that outcome is significantly affected by host genetic factors.
Inflammation and susceptibility to neurodegeneration: The use of unbiased genetics to decipher critical regulatory pathways
2009, Neuroscience
Neurodegeneration and signs of immune activation, with T cell infiltration, major histocompatibility complex class II expression and glial activation, occur in many neurological diseases. Although particular qualities of the inflammatory response have been proposed to be of importance, still very little is known about the exact factors that determine susceptibility to neurodegeneration. Mechanistic studies have yielded conflicting results, where inflammation is suggested both to attenuate and aggravate loss of nerve cells depending on the circumstances. In this context experimental genetic dissection in relevant rodent models such as experimental autoimmune encephalomyelitis and mechanical nerve injury can be a valuable tool to identify important genes/molecules/pathways. We here review emerging evidence using this approach that indicates different pathways related both to adaptive and local innate immune responses, which determine strain-specific susceptibility to neuroimmune inflammation and neurodegeneration. Exact positioning of genes in these types of complex traits will be important for the understanding of pathogenetic mechanisms and to direct the focus of functional studies using classical experimental tools. Ultimately, a better knowledge about the interplay between the nervous system and the local and systemic immune system can define new ways of intervention in neurodegenerative processes.
Protective autoimmunity in the nervous system
2009, Pharmacology and Therapeutics
The immune system can play both detrimental and beneficial roles in the nervous system. Multiple arms of the immune system, including T cells, B cells, NK cells, mast cells, macrophages, dendritic cells, microglia, antibodies, complement and cytokines participate in limiting damage to the nervous system during toxic, ischemic, hemorrhagic, infective, degenerative, metabolic and immune-mediated insults and also assist in the process of repair after injury has occurred. Immune cells have been shown to produce neurotrophic growth factors and interact with neurons and glial cells to preserve them from injury and stimulate growth and repair. The immune system also appears to participate in proliferation of neural progenitor stem cells and their migration to sites of injury. Neural stem cells can also modify the immune response in the central and peripheral nervous system to enhance neuroprotective effects. Evidence for protective and reparative functions of the immune system has been found in diverse neurologic diseases including traumatic injury, ischemic and hemorrhagic stroke, multiple sclerosis, infection, and neurodegenerative diseases (Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis). Existing therapies including glatiramer acetate, interferon-beta and immunoglobulin have been shown to augment the protective and regenerative aspects of the immune system in humans, and other experimental interventions such as vaccination, minocycline, antibodies and neural stem cells, have shown promise in animal models of disease. The beneficent aspects of the immune response in the nervous system are beginning to be appreciated and their potential as pharmacologic targets in neurologic disease is being explored.
Spinal Cord Injury: Experimental animal models and relation to human therapy
2009, The Spinal Cord
The majority of spinal cord injury (SCI) events occur in the 18–35 year age group and the long-term personal, social and economic costs are enormous. Increasing use is being made of experimental animal models of SCI. The aims are to better understand the acute and chronic morphological, cellular and molecular consequences of SCI, and with this information develop and test new therapies to enhance anatomical repair and functional recovery. The ultimate aim is improved treatment and rehabilitation of patients suffering SCI. As the goal for clinical therapies becomes increasingly reachable, associating these often broad behavioral outcomes with experimental strategies aimed at tissue repair/sparing, remyelination, neuronal protection, cellular replacement, and axonal regeneration, as well as the activation of endogenous host stem/progenitor cell responses, has become more crucial but also more complex. There are many differences between the nervous systems of humans and animals commonly used in SCI studies. Issues such as size, gait, neuroanatomical, neurophysiological, and behavioral differences as well as disparities in immunological and inflammatory responses following SCI, all point to potential limitations of animal models when assessing the efficacy and safety of possible SCI treatments in humans. Use of non-human primates as an intermediate step between rodents and humans may aid in translation of effective therapies to the clinic.
The role of T helper cells in neuroprotection and regeneration
2007, Journal of Neuroimmunology
The inflammatory wound healing response of the central nervous system (CNS) following mechanical injury is characterized by at least one or two phases of T cell infiltration. Surprisingly, whether T cells play a beneficial or detrimental role in these processes is still controversial. It has been suggested that autoimmune T cells may provide “protective autoimmunity”, however, after CNS injury, injections of autoimmune T cells and vaccine strategies led to both improvement in some models and exacerbation of the damage in others. Here, we review increasing evidence that a specific T cell subpopulation, namely T helper cells type 2 (Th2 cells) are particularly beneficial in the context of CNS lesions. CNS injuries such as mechanical lesions or stroke induce a systemic immunosuppression, which is characterized by a systemic shift towards a Th2 cytokine pattern. Simplified, this systemic Th2 shift results in reduced cell-mediated immune responses, and, to a lesser extent, humoral immune responses. Furthermore, treatment with potent Th2 inducers such as glatiramer acetate or statins, as well as vaccination strategies using Th2-inducing adjuvants for immunization such as aluminum hydroxide, result in increased neuroprotection and regeneration — without development of autoimmune CNS inflammation. Thus, it is tempting to speculate that a systemic Th2 shift is part of a necessary CNS wound healing response after injury, by furthering regeneration and preventing autoimmune disease of the CNS. Within this context, investigating the potential of a systemic Th2 shift to improve outcome after CNS injury, including the control of possible side-effects such as increased susceptibility to infection and allergic responses, is extremely promising.

View all citing articles on Scopus

¹: Dr. Jia-Bin Sun is a guest scientist from the Department of Neurology, First Hospital, Harbin Medical University, China.

View full text

Research articleAutoreactive T and B cell responses to myelin antigens after diagnostic sural nerve biopsy

Abstract

J. Immunol. Methods

J. Neuroimmunol.

Brain Res.

J. Biol. Chem.

J. Neuroimmunol.

J. Neurol. Sci.

J. Neuroimmunol.

Biochim. Biophys. Acta

J. Neuroimmunol.

Molecular transductional mechanisms by which IFN-γ and other signals regulate macrophage development

Immunol. Rev.

Technique of sural nerve biopsy

The rapid isolation of clonable antigen specific lines capable of mediating autoimmune encephalomyelitis

Eur. J. Immunol.

Genetic control of autoimmune encephalomyelitis and recognition of the critical nonapeptide moiety of myelin basic protein in guinea pigs are exerted through interaction of lymphocyte and macropahges

Eur. J. Immunol.

Detection of single antibody-secreting cells generated after in vitro antigen-induced stimulation of human peripheral blood lymphocytes

Scand. J. Immunol.

Large scale preparation of myelin basic protein from central nervous tissue of several mammalian species

Prep. Biochem.

Interferon-gamma regulates an antigen specific for endothelial cells involved in lymphocyte traffic

The role of interferon-gamma in the pathogenesis of experimental autoimmune disease of the peripheral nervous system

Ann. Neurol.

Reciprocal expression of interferon γ or interleukin 4 during the resolution of progression of murine leishmaniasis

Evidence for expansion of distinct helper T cells

J. Exp. Med.

Chronic experimental autoimmune encephalomyelitis induced by the 89–101 myelin basic protein peptide in B10RIII (H-2r) mice

Eur. J. Immunol.

Detection of intracellular expression and secretion of interferon-γ at the single cell level after activation of human T cells with tetanus toxoid in vitro

Eur. J. Immunol.

Substitute for benzidine in myeloperoxidase stains

Am. J. Clin. Pathol.

CD4+ suppressor

cells inhibit the function of effector cells of experimental autoimmune encephalomyelitis through a mechanism involving transforming growth factor-β

J. Immunol.

A permanent rat T cell line that mediates experimental allergic neuritis in the Lewis rat in vivo

J. Immunol.

Research article
Autoreactive T and B cell responses to myelin antigens after diagnostic sural nerve biopsy

Chronic experimental autoimmune encephalomyelitis induced by the 89–101 myelin basic protein peptide in B10RIII (H-2^r) mice

CD4⁺ suppressor