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Chronic Inflammatory Demyelinating Polynueropathy (CIDP)

Figure 1: This illustrating shows nerve demyelination in a disorder similar to CIDP: Multifocal Motor Neuropathy (MMN).

Myelinated Axons: Segmental demyelination in Multifocal Motor Neuropathy (MMN)

Permission to use this figure was requested from Washington University. If permission is denied the figure will be removed.(http://www.neuro.wustl.edu/neuromuscular/antibody/pnimdem.html)

Introduction to Autoimmunity:

Autoimmune disease occurs when the immune system initiates a specific adaptive response to a self protein (Janeway, 2001). They are a direct result of the open range of specificity existing on B-cell and T-cell receptors allowing them to recognize any antigen entering the body. This wide range of recognization comes at a small price, due to the mechanisms in place to prevent self-reactivity. The result of this specificity is contra-indicated only if something goes wrong in the normal pathway. This can occur through several methods: The method hypothesized to be at work in CIDP is the representation of self peptide as well as antigen peptide on a cell's surface prompting the survival signal for lymphocytes and allows them to make antibodies and T-cells specific for the infection as well as the self-protein.

Once autoimmunity has been established, the ongoing problem of the inability for the immune system to shut off the self-reactive response because the effector mechanisms cannot be completely eliminated creates a chronic problem. In CIDP, however, there is no indication that persistent antigen stimulation is related to the chronic nature of the disease ( van Doorn, 2000). The result of the constant activation of effector pathways is chronic inflammation which can prove lethal to affected tissues (Janeway 2001).

This disease is characterized by progressive weakness and loss of neurological function primarily in the legs and arms (NINDS, 2001). Most patients with this disorder present with a case of progressive weakness for at least two months (van Doorn, 2000), the temporal indicator of the chronic form of this neuropathy. The course of the disease tends to be either slow and gradual, or characterized by periods of relapses and remissions (van Doorn, 2000). Although this disease is slightly more prevalent in young adults, it can occur at any age, and statistics show that men are twice as likely as women to contract this disease (NINDS, 2001). Some typical symptoms include: symmetric tingling in the proximal and distal extremities, paralysis of the muscles, progressive weakness, sensory loss, loss of nero-muscular reflexes, and frequent loss of balance. It is not uncommon for a CIDP patient to to lose the ability to feel the sharp sensation of a pin stick in the affected area.This onset is prolonged and gradual over the course of at least 8 weeks (Koski, 2002). Statistics show that 70% of patients diagnosed with CIDP presenting only sensory symptoms develop motor symptoms over the course of 2-3 years (Koski, 2002).

Note: Permission to use this figure has been requested from the Department of Neurology at Baylor College of Medicine. If permission is denied the figure will be removed.

Figure 2: This figure shows a representation of a demyelinated nerve

A. Demyelination at the paranodal region (solid arrow). Arrow head points to the node of Ranvier.

B. Demyelination of a nerve segment (solid arrow) between the two nodes of Ranvier (arrow heads). This finding is frequently observed in the nerve biopsy of CIDP.

The main reason CIDP is considered an immune disorder is that it responds to immune-mediated treatment (Koski, 2002). It is very difficult to diagnose and can be diagnosed through a number of methods which are discussed below. Although the aetiology remains unknown, both humoral and cell-mediated immune mechanisms contribute to the pathogenesis ( Mahad, et al, 2002).Immune or inflammatory mechanisms are thought to be the root cause of many disorders that, like CIDP, reflect damage to the peripheral nerves and affect sensory function. This turns out to be the most definite role of the immune system in the development of CIDP; the mutation of the macrophage to cause macrophage-mediated inflammation, ultimately resulting in the demyelination of the nerves.
Another characteristic of CIDP, which leads to its classification as an autoimmune disorder, is the evidence of preexisting infections immediately prior to the development of the disease in a significant number of patients. Studies show that in 70% of GBS patients (Guillain-Barre Syndrome), the acute form of CIDP, have pre-existing infections prior to the development of symptoms. Although the pathology of the infections preceding CIDP are studied less frequently, statistics show that at the very least relapses are strongly correlated with infection (van Doorn, 2000).

The specific pathway for induction of the autoimmunity associated with CIDP is unknown. The current research cannot eliminate the possibility of an antibody mediated self-reactivity or a T-cell mediated self reactivity (van Doorn, 2000). The possibility that infection is a possible stimulus to the development of CIDP can support either pathway (Janeway, 2001). Infections are capable of inducing co-stimulatory activity on antigen presenting cells that present low levels of the specific peptide being attacked, in this case myelin. Another pathway is that of molecular mimicry. In this situation, antibodies or T-cells generated in response to an infectious agent cross-react with self antigens (Janeway, 2001). A molecular mimic is a foreign antigen closely related in structure to a self peptide allowing an antibody mediated response mounted toward the mimicked peptide to also effect the self-protein (Janeway, 2001).

What components of the immune system are involved?

T-Cells:

The most widely explained mechanism for the demyelination of nerve cells in CIDP is a macrophage-mediated inflammatory response.Endoneurial inflammatory changes with T cell infiltrates and macrophage associated demyelination are present on nerve biopsies in patients in the acute phase of CIDP (Mahad, et al, 2002). These endoneurial lymphocytes are associated with the increase expression of mRNA for Tumor Necrosis Factor alpha (TNF alpha), Interferon gamma (INF gamma) and Interluekin-2 (IL-2) (Mahad, et al, 2002).. TNF alpha is involved in local inflammation and endothelial activation. INF gamma causes macrophage activation, increased expression of MHC molecules and Ig class switching. INF gamma also suppresses the less damaging TH2 response in favor of the inflammation mediation of TH1. IL-2 is a crucial chemokines for the adaptive immune response and aids in the proliferation of T-cells. All of these proteins are either produced by T-cells, Natural Killer Cells or Macrophages, or add to the existence of T-cells and cause the initial inflammatory response associated with infection (Janeway, 2001). Activated T lymphocytes are increased in the peripheral blood of CIDP patients. This diagnostic evidence coupled with the relative success of T-cell suppressive treatment makes the case for a possible malfunction in the TH1 inflammatory response.

Antibodies and Complement:

These components of the immune system play a role in the pathogenesis of CIDP in the presence of a blood-nerve barrier breakdown. (after the demyelination has begun)

The current research debates whether CIDP is associated with a specific antibody response against neural antigens (van Doorn, 2000). Antibodies against selected neuroblastoma cells have been found in 40% of patients with CIDP and GBS in comparison with only 4% in other neuropathies (van Doorn, 2000). This, however, is far from conclusive as to the direct pathology of the disease, as other groups show no antibody interaction with myelin proteins or glycolipid cell-surface receptors (van Doorn, 2000).

Some forms of CIDP can be diagnosed using autoantibody serums to tubulin. Tubulin is a molecule which mediates many cell processes specifically cell division and movement of materials within cells. The suggested mechanism for the autoantibody to tubulin involves both IgG and IgM antibodies capable of binding to the tubulin epitope. This pathology was present in 10% of patients with CIDP (Washington University, 2003).

Another specific immunologic interference occurring in 26% of patients with CIDP is an interaction between IgG antibodies and Schwann cell processes. Schwann cells are the cells that wrap themselves around nerves making a protective barrier for the nerve fibers. Schwann cells are the individual cells making up the myelin protective sheaths. This suggests that a patient presenting with symptoms of CIDP could possibly have an autoantibody response against cell schwann cells. This response tags the self-protein for natural killer cell destruction.