Case 30

Published on 18/02/2015 by admin

Filed under Allergy and Immunology

Last modified 22/04/2025

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CASE 30

Sam is a 44-year-old, previously healthy man who has been suffering from blurred vision and intermittent numbness in the left leg and right arm for 7 months. Over the past 4 weeks he has been incontinent of urine twice. His male companion is convinced he has a brain tumor or some other sinister disorder. All of his routine blood work is normal, as is his urinalysis, antinuclear antibody (ANA) titers, and complement C3 levels. His last HIV test (6 years ago) was negative, and he has lived with his current partner for more than 5 years. A repeat HIV test is negative.

QUESTIONS FOR GROUP DISCUSSION

1. Review the types of infection that cause chronic infection of the central nervous system (CNS) or encephalitis. What single piece of evidence would reduce the likelihood that Sam has an infection or a multifocal brain tumor?

2. Systemic lupus erythematosus (SLE) cerebritis might present in this manner. Review Case 18 and explain why this disorder might lead to cerebritis. How would you rule out SLE?

3. What disorders are associated with urine incontinence in males?

4. Multiple sclerosis (MS) is a waxing/waning disease that manifests at different sites, and so this disorder should be the focus of investigation. Explain how magnetic resonance imaging (MRI) and magnetic resonance spectroscopy could help in the diagnosis of MS. What would a biopsy show?

5. Oral feeding of antigen (bovine myelin) has been used as a therapeutic intervention in some clinical trials of patients with MS. Explain the rationale for this approach.

6. Explain why chemokine antagonists are being considered as therapeutic agents in MS. (Hint: review Case 23.)

7. Explain tolerance induction and how this might be achieved in patients with MS.

8. Discuss the pros/cons of targeting specific Vβ T cells as therapy for patients with MS.

9. What antibody isotype(s) is (are) found in the CSF of patients with MS? In the serum?

10. Review the steps of delayed-type hypersensitivity (DTH). Note, in particular, the role of interferon gamma (IFNγ). Explain why IFNγ would exacerbate MS.

RECOMMENDED APPROACH

Implications/Analysis of Family History

Although we are not provided with any family history, there is a genetic susceptibility for MS. However, risk for this autoimmune disorder involves more than gene inheritance. For example, living in a temperate zone (both north and south of the equator) has been shown to be a risk factor for MS. However, even within the same temperate climate the prevalence of MS is higher in whites.

Implications/Analysis of Clinical History

The altered vision and intermittent numbness in Sam’s arm and leg are indicative of multiple, distinct sites in the nervous system and lead one to consider a multifocal brain tumor. However, the fact that the altered vision and changes in sensation are also occurring at different points in time suggests we are dealing with a waxing/waning disease entity, which is not characteristic of tumors but should make you think of other causes, especially immunologic ones.

Infection

Toxoplasmosis (and other chronic CNS infections [e.g., Cryptococcus neoformans]) could present as a multifocal disease. One might expect viral encephalopathies (e.g., herpes simplex virus, also referred to as human herpesvirus 1) to present more acutely than over months. Again, infection is unlikely to be intermittent. Immune complex deposition disease (lupus cerebritis) such as occurs in systemic lupus erythematosus (SLE), is a possibility because it is associated with intermittent inflammation in the CNS (see Case 31).

Urine Incontinence

The urine incontinence is puzzling in that Sam does not appear to have an infection and is not taking medications known to affect continence. In men, diabetic neuropathy, MS, and Parkinson’s disease are known to be causes of incontinence. There is no evidence of diabetes or Parkinson’s disease, but the symptoms of blurred vision and changes in sensation are consistent with a diagnosis of MS.

Implications/Analysis of Laboratory Investigation

His last HIV test (6 years ago) was negative, and a repeat test is negative, ruling out HIV-related neurologic disease. All of Sam’s routine blood work is normal, as are his ANA titers and complement C3 levels, ruling out lupus cerebritis (see earlier). Having excluded SLE, viral infection, and diabetes, we are faced with the fact that there are multiple neurologic insults that manifest as a clinical symptom intermittently. The most plausible disease based on both exclusion and clinical presentation is MS.

Additional Laboratory Tests

There is no definitive diagnostic test for MS. A positive diagnosis requires that a number of criteria be fulfilled. MRI that reveals four distinct white matter lesions (or three if one is periventricular) is a criterion supporting an MS diagnosis. Results of Sam’s MRI evaluation revealed multiple lesions with no ring enhancement after administration of a contrast agent (which is typical of “walled off” tumor/cryptococcal/ and Toxoplasma lesions). Magnetic resonance spectroscopy may be used to detect biochemical changes in the brain by following the levels of N-acetyl-aspartate (NAA), an amino acid found in neurons and axons. A reduction in NAA is indicative of axonal loss. This technique provides information regarding decreased activity in areas of the brain without lesions and so can be used to monitor the progression of MS. A biopsy revealed nonspecific inflammation with activated glial cells and lymphocyte infiltration.

DIAGNOSIS

Sam was diagnosed with multiple sclerosis.

THERAPY

At present, neither prednisone nor cyclophosphamide (potent anti-inflammatory agents) have proven to have the desired efficacy, and there is clearly a need for newer therapies, including investigational ones.

Oral Feeding of Antigen

One therapy that has incited great interest involves oral feeding of CNS antigens, which may be relevant to the disorder! Why would further antigen exposure be considered as a way of improving disease outcome, rather than making it worse? The rationale lies in the belief that pathology is secondary to Th1-driven cytokine production. If this is the case, “switching” T cell activation to Th2 cytokines might be beneficial. Transforming growth factor-β (TGFβ) and interleukin-10 (IL-10) are two cytokines that can alter this balance of Th cells from Th1 to Th2. The production of both these cytokines is increased (we do not know how) after oral immunization. Presumably, this has something to do with unique modes of antigen presentation in the gut. The expectation is that increased TGFβ and IL-10 will “switch off” cytokine production by Th1 cells, increase Th2 cytokine production, and thus lead to improvement of symptoms in MS. To date the results of clinical trials have not been very impressive.

One of the reasons for these disappointing results may lie in the fact that several studies have been published suggesting that Th2 cytokines also play a role in the pathogenesis of MS.

Chemokine Antagonists

Other notable changes occur within the CNS of MS patients, perhaps even before altered cytokine production. Included in the changes are altered production of certain chemokines, chemical messenger molecules that control a myriad of functions, including leukocyte migration, endothelial activation, cytokine production, and even lymphocyte activation. Thus, treatment with chemokine antagonists may prove beneficial.

Restoring Tolerance

In animal model systems, therapies aimed at restoring tolerance have shown some promise. The “targets” in this approach are T lymphocytes expressing T cell receptors specific for MS peptide and class II MHC proteins (i.e., class II MHC/MS peptide). This is accomplished by introducing altered MS peptides that will be presented to T cells in the groove of class II MHC proteins on antigen-presenting cells. The expectation is that the altered peptide will trigger signals that inhibit further T cell activation. Consequently, these T cells undergo apoptosis and result in nonresponsiveness to the class II MHC/MS peptide (i.e., tolerance).

Monoclonal Antibodies

In another approach, CD4+ T cells are targeted with monoclonal antibodies so that complement or phagocytes can destroy them. The specificity of the monoclonal antibodies is the particular Vβ segment present in the T cell receptors that recognize the class II MHC/MS complex (see Case 2). The downside to this approach is that many T cells specific for other peptide-MHC complexes also express that particular Vβ segment and so all of these T cells would also be destroyed.

A more pervasive deletion of immune cells can be accomplished by the deletion of leukocytes (which would include T cells) using a monoclonal antibody (alemtuzumab) specific for the leukocyte marker, CD52. The downside to this type of therapy is that all leukocytes are potential targets for elimination. A clinical trial using this monoclonal antibody is currently in progress in both the United States and Europe.

ETIOLOGY: MULTIPLE SCLEROSIS

MS is a chronic inflammatory disease of the CNS that results in scarring and demyelination (Fig. 30-1). There is evidence that a breakdown of tolerance to a variety of nerve-associated proteins/glycolipids plays a major role in the disease process. CD4+ T cells, secreting type 1 cytokines, have been the focus of investigations and novel therapies for MS. More recently, however, a role for type 2 cytokines (and CD8+ T cells) in the disease process has been proposed. Autoantibodies specific for myelin basic protein are generated in MS, but these are not thought to be the inciting agents of disease. They do, however, contribute to the pathogenesis of disease because their presence can activate phagocytes and complement processes.

FIGURE 30-1 Multiple periventricular lesions seen in MR image of patient with late-stage multiple sclerosis.

Risk for Acquiring MS

From a genetic point of view, HLA-DR2 is a major risk factor for developing MS. Obviously, the contribution of genetic inheritance is best determined with monozygotic twins, which shows a concordance rate of 30%. Siblings and other relatives have an increased risk for disease, but this risk decreases as genetic similarity decreases. So, even though first-, second-, and third-degree relatives are all at risk, third-degree relatives would have the lowest risk (see earlier for risk associated with living in a temperate zone).

Immunoglobulin Profiles in CNS and Serum

CD4+ T cells recognize unique CNS antigens (e.g., myelin basic protein), and cytokine production from these T cells activates local inflammatory processes. Note that when cells in the immune system are activated by specific antigen, only T and B cells recognizing that particular antigen will proliferate. This results in so-called oligoclonal activation, not polyclonal activation.

In this case, the immunoglobulin profile in the CNS shows an oligoclonal pattern of IgG synthesized in the CNS. Various techniques are used to ascertain that these IgG antibodies are not serum antibodies that have crossed into the CNS. In contrast, all antibody isotypes are represented in serum. These antibody isotypes can be separated using immunoelectrophoresis; and because of the polyclonal nature of the antibodies in this disease, the pattern is smeared.

T Cell Receptor Specificity

In the T cell compartment, specific stimulation leads to recruitment of T cells expressing only some Vβ molecules in their antigen receptor. Again, Vβ analysis of T cells after specific stimulation will show oligoclonal expansion of the Vβ repertoire. Similarly, CNS T cells show limited Vβ patterns (oligoclonal activation).

Inciting Agent(s)

There often is evidence for both immunoglobulin and T cell reactivity to antigens that cross react with “measles-like” antigens, providing the basis for the belief that there may be a viral inciting agent as the cause of this disease. The geographic distribution of this virus might explain the preponderance of MS in those individuals born in the temperate zones.

Cytokine Production and a Delayed-Type Hypersensitivity Reaction

An inflammatory delayed-type hypersensitivity reaction (DTH) picture is characteristic of Th1 activation. Thus, in most circumstances you can expect to see evidence for IL-2, IFNγ, and tumor necrosis factor-α (TNFα) production. With effective treatment, production of these inflammatory-type cytokines decreases. The difficulty is in finding an effective treatment!

Interestingly, IFNγ was initially used as a therapy for MS, but it exacerbated the disease, despite the fact that it reduced symptoms in animal models. More puzzling is the fact that therapies that neutralize TNFα have induced inflammatory demyelination. Until recently, most studies supported a model in which disease process was due to the presence of type 1 cytokines and that the disease process could be ameliorated by enhancing the production of type 2 cytokines that downregulate type 1 cytokine production.

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