The role of autoantibodies in health and disease.

Serum of healthy individuals contains antibodies that react with self and non-self antigens, generated in absence of external antigen stimulation. These antibodies, called natural antibodies, are particularly IgM isotype, are considered natural autoantibodies (NAA), displaying a moderate affinity for self-antigens. Although incidence of NAA in healthy individuals is not reported, it is established that autoreactive antibodies and B-cells, as well as autoreactive T-cells, are present in healthy persons. The functional abilities of NAA are not clear but is well accepted that they may participate in a variety of activities, such as maintenance of immune homeostasis, regulation of the immune response, resistance to infections, transport and functional modulation of biologically active molecules. On the other hand, specific adaptive immune responses through high-affinity, class-switched IgG autoantibodies, which bind self-proteins, can cause tissue damage or malfunctions, inducing autoimmune diseases. The new technology that allows for more autoantibody screening may further enhance the clinical utility of autoantibody tests, making it possible to diagnose autoimmune disease in its early stages and to intervene before installing injuries. The aim of this review paper is to succinctly analyze the progress in the physiological role and regulatory significance of natural autoantibodies in health and disease.

Intravascular Lymphomatosis Presenting as Skin Lesions and Subacute Encephalopathy.

Intravascular lymphomatosis is a neoplastic multisystemic disease; it is a rare subtype of diffuse large cell lymphoma characterized by the presence of lymphoma cells in the lumina of small vessels. A 49-year-old Caucasian woman was admitted to the Department of Internal Medicine for fatigue, night sweats, loss of weight, and multiple nodules in the forearms. Three months ago the patient's family noticed problems with her cognitive function, she displayed difficulties with common daily tasks. The neurological examination revealed bradypsychia. Laboratory data showed modestly high levels of lactate dehydrogenase, and C-reactive protein. The day after admission, the patient had headache which raised in intensity; his mental status deteriorated, she was disoriented to time and place. She presented nucal rigidity. The CSF examination revealed a hemorrhagic aspect, elements 30/mm3, cytology: lymphocytes 90%, numerous erythrocytes, proteinorachia 96 mg/dL, glycorrachia 60 mg/dL. Intravenous Methylprednisolone (0.5 g two times a day) and Mannitol 20% 1g/kgw/day were administered for five days without response. She became comatose and she died six days after hospitalization. The post-mortem macroscopical brain examination showed a swallen brain, with diffuse hemorrhagic areas in the supratentorial subcortical regions. Microscopical examination showed capillaries, venules, and many arterioles distended by large malignant cells suggesting malignant lymphocytes which were intraluminal. Every organ was involved, except for bone marrow and lymph nodes. Immunohistochemical studies showed intensive staining for B cells. and negative staining for factor VIII related antigen, a specific endothelial cell marker. Intravascular lymphomatosis was the post-mortem diagnostic. It represents a difficult diagnostic challenge which involves laboratory, imagistic and immunohistochemical investigations.

Meningeal carcinomatosis in a patient with Crohn's disease.

Leptomeningeal carcinomatosis, also known as carcinomatous meningitis, is defined by spreading of neoplastic cells to the meninges and ventricles, and is a form of cancer dissemination. In this case, a patient with inflammatory bowel disease had developed a neoplastic process that spread to the meninges. A 49-year-old woman developed an abdominal pain, and was diagnosed the same month with Crohn's disease, complicated with intestinal perforation, for which she was hospitalized. Pathological examination revealed acute phase-terminal ileitis. She undergone many hospitalizations during which she was suspected to have celiac disease, inflammatory bowel disease, and tuberculous meningitis, as well as femoral head necrosis after she had been unsuccessfully treated with Prednisone for Crohn's disease. After she developed peripheral bilateral facial paresis, bilateral hypoacusia, hypotonia, tetraparesis and diminished osteotendinous reflexes at the legs, the patient was admitted in our department. Several lumbar punctures were performed but no specific disease could be detected. The MRI performed showed pachymeningeal and leptomeningeal inflammation. Tuberculous meningitis was taken into consideration and the patient was transferred into an Infectious Disease Department where this diagnostic was infirmed. The patient was retransferred into the Department of Neurology where after an episode of hematemesis she had a cardiac arrest and deceased. Inflammatory bowel disease may involve different segments of the intestine, and may be accompanied by a variety of conditions, such as neurologic findings, osteoarticular manifestations and also may be the starting point of a neoplastic process. The patient had an inflammatory bowel condition, which by the time it was appropriately diagnosed as being Crohn's disease, a neoplastic process spread to the meninges, causing multiple cranial nerve palsy, tetraparesis, along other neurological manifestations.

Cerebrovascular complications in patients with inflammatory bowel disease.

UNLABELLED: Cerebrovascular complications in 9 patients with inflammatory bowel disease (IBD) are presented, 6 with Crohn's disease (CD) and 3 with ulcerative colitis (UC), 7 men and 2 women, mean age 36.5 +/- 3.5 years, 4 of them during acute disease. Cerebrovascular complications were: cerebral venous thrombosis (CVT)--7 cases (5 CD and 2 UC) and ischemic stroke--2 cases (1 CD and 1 UC). Out of 7 cases with CVT 5 were superior sagittal sinus thrombosis (SSS), 2 SSS and transverse and sigmoid sinus thrombosis. Both ischemic strokes were infarctions in the middle cerebral artery area. No correlation between high doses of corticosteroids or their lowering, IBD activity, duration of the disease, and the appearance of cerebrovascular complications was observed. Tendency to hypercoagulation even in the inactive stage of the IBD was revealed. Investigations for thrombophilia were negative. Significantly high levels of homocysteine were observed in all patients. CONCLUSION: Neurovascular complications may be observed in IBD, both of venous and arterial type. Pathogenic mechanisms of these vascular complications are complex, low serum folate levels, of vitamin B6 and B12 being associated with elevation of homocysteine levels, high activation of platelets and microvascular endothelial dysfunction. A guide for the orientation of prophylaxis of cerebrovascular complications in IBD patients is necessary.

Matrix metalloproteinases (MMP-3 and MMP-9) implication in the pathogenesis of inflammatory bowel disease (IBD).

Inflammatory bowel disease is a chronic disease, with unknown etiology, characterized by a sustained inflammatory cascade that gives rise to the release of mediators, capable of degrading and modifying bowel wall structure. The present study investigated changes of circulating metalloproteinases (MMP-3, MMP-9) and CRP levels in patients with ulcerative colitis and Crohn's disease, in order to contribute to the elucidation of pathogenesis. We have studied serum samples of 67 patients, of which 46 with ulcerative colitis (mean age 44.8 years) and 21 affected by Crohn's diseases (mean age 39.52 years), who were hospitalized in the Clinic of Gastroenterology of the Emergency County Hospital of Craiova, Romania. For the quantitative determination of MMP-3, MMP-9 and CRP, the ELISA technique was used. Both patients, with Crohn's disease and ulcerative colitis, showed increased production of studied immunomarkers, which were correlated with some clinical stages, indicating their involvement in the disease activity.

A diagnosis challenge-L4 nerve root compression as the initial presentation of chronic inflammatory demyelinating polyneuropathy.

The authors present the case of a 65-year-old woman who was admitted for paraparesis and paresthesias in the inferior limbs. The neurological examination revealed the difficulty in extension of the right foot and of the right toe, accompanied by paresthesias located in the anterolateral area of the right leg, dorsum and plantar area of the foot, the reduction of the right knee jerk, and of the ankle tendon jerk both sides. The vertebro-spinal MRI showed lumbar canal stenosis with L4 intraforaminal compression on the right, and L2-L3 on the left. CSF examination revealed mild increase in protein concentration. The morphological picture of the sural nerve biopsy was compatible with a chronic inflammatory neuropathy and severe muscular lesions of neurogenic origin were observed on right gastrocnemius muscle biopsy. The diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) was established. Solu-medrol (0.5 g/d)-5 days, then medrol (prednisolone) was done, followed by improving of the symptomatology. For the relapse of the disease intravenous immunoglobulins (IVIG)-0.4 g/kg/d-5 days was the elective treatment. Six months later she presented a new relapse. IVIG were administered with the remission of the sensitive symptoms. A chronic treatment with medrol was recommended. The diagnosis of L4 disc herniation was obvious in the studied case, but the electroneurographic examination brought extra data for the associated diagnosis of CIDP whose onset was asymmetrical and initially paucisymptomatic. Neither the electroneurographic examination nor the CSF examination were total relevant for CIDP, imposing the sural nerve biopsy. The diagnosis of CIDP involves a team-work composed of neurologist, electroneurophysiologist and neuropathologist.

Study of interleukin-6 production in Alzheimer's disease.

There is a growing body of evidence which supports the hypothesis of faulty immune regulation and autoimmunity or inflammatory processes as viable mechanisms of the pathogenesis of Alzheimer's disease. The aim of this study was to evaluate the IL-6 level in serum of patients with AD and to analyze the correlation between IL-6 and this disease. Serum samples from 47 patients with clinically diagnosed Alzheimer's disease (27 women and 20 men, mean age 70.43 +/- 10.82 years, range 40-89 years) as compared to 47 controls (25 women and 22 men, mean age 70.17 +/- 10.64 years, range 40-89 years) were analyzed for IL-6 by ELISA (R&D Systems). The interleukin-6 levels were significantly higher in AD patients (234 pg/ml, range 85-567 pg/ml) as compared to control group (67 pg/ml, range 38-181 pg/ml); p < 0.001. It was evident from the study that increased production of IL-6 cytokine is found in AD patients, suggesting abnormal cellular immunity in these patients. Interleukin-6 plays a role in the pathogenesis of Alzheimer's disease. Our results suggest that high peripheral IL-6 secretion levels may be responsible for acute-phase proteins observed in the serum of AD patients. We find these results very promising for the consideration of future treatment of AD patients.

Gastrointestinal manifestations in systemic autoimmune diseases.

In an autoimmune disease, the immune system attacks and harms the body's own tissues. The systemic autoimmune diseases include collagen vascular diseases, the systemic vasculitides, Wegener granulomatosis, and Churg-Strauss syndrome. These disorders can involve any part of the gastrointestinal tract, hepatobiliary system and pancreas. They can cause a variety of gastrointestinal manifestations that are influenced by the pathophysiologic characteristics of the underlying disease process. There is a wide variation of gastrointestinal manifestations from these autoimmune disorders including, but not limited to: oral ulcers, dysphagia, gastroesophageal reflux disease, abdominal pain, constipation, diarrhea, fecal incontinence, pseudo-obstruction, perforation and gastrointestinal bleeding. Clinical workup should be initiated by the patient's subjective complaints. In this review, we analyze the effects of autoimmune diseases on the gastrointestinal tract.

Primary Sjögren's syndrome or multiple sclerosis? Our experience concerning the dilemma of clinically isolated syndrome.

The authors present the case of a 50 years old woman who during 3 years had a transient right limbs palsy, and numerous episodes of unilateral/bilateral optic neuropathy. The CSF and MRI examinations did not sustain the diagnosis of multiple sclerosis (MS). After 2 years from the onset, she presented bilateral trigeminal neuropathy, and after 9 months the anti-SS-A and anti SS-B antibodies were positive. The sialography and the minor salivary ducts biopsy (in the absence of xerostomia and xerophthalmia) have established the diagnosis of primary Sjögren's syndrome (pSS). Subsequently, the patient presented spastic paraparesis, the clinical and imagistical features have suggested the diagnosis of acute transverse myelitis C4-T4. The treatment administered (corticosteroids and IGIV) improved the clinical state. The authors analyse then cases with SLE and cases with pSS, whose initial diagnosis was MS possibly with no evidence of collagen tissue disorders (CD) for many years. In conclusion, screening for biomarkers of SLE or pSS should be systematically performed in a case of acute or chronic myelopathy. Some laboratory tests as CSF examination, the antibodies type, cranial and spinal MRI, are useful for the differential diagnosis with MS. In a neurological clinically isolated syndrome (CIS) the diagnosis of MS should be precautiously established; the close follow-up of patients is always necessary, those with atypical neurological symptoms for MS, relapsing-remitting form, or lack of response to the common treatment for MS, should be examined for CD.

Pulmonary manifestations of systemic autoimmune diseases.

Systemic autoimmune diseases (SAD) are a heterogeneous group of immunologically mediated inflammatory disorders including multiorgan involvement. As expected in a multisystem disease, the entire pulmonary system is vulnerable to injury. Any of its compartments may be independently or simultaneously affected. It is difficult to assess the true prevalence of lung disease in cases of SAD. In this article, we will review the pulmonary manifestations caused by systemic lupus erithematosus, rheumatoid arthritis, systemic sclerosis, polymyositis/dermatomyositis, Sjögren's syndrome, mixed connective tissue disease, Wegener's granulomatosis, Churg-Strauss syndrome, Goodpasture's syndrome, and ankylosing spondylitis.

Dermatomyositis and polyradiculoneuritis, a rare association.

The association between dermatomyositis and polyradiculoneuritis is rarely citated in the speciality literature. Our patient had at first a disorder that looked like dermatomyositis, then she associated polyradiculoneuritis. At the presentation to our hospital the two diseases were combined, being very difficult to differentiate. The discrimination between these two had been made by performing a muscular biopsy and EMG studies. This emphasizes once again their importance in defining the muscular impairment from the neurogenic one.

Expression of IL-6 activity in patients with acute ischemic stroke.

Cerebral ischemia initiates an inflammatory response in the brain and periphery. Inflammatory mechanisms, including IL-6, are suspected to play a role in arterial thrombogenesis. Their presence in the periphery is still controversial. The question arises as to whether IL-6 might directly contribute to cerebral infarct pathogenesis. IL-6 has several pro-inflammatory effects which may contribute to the induction and evolution of early inflammatory injury in the brain and its vasculature. The objective of this study was to test the hypothesis that there is a relationship between inflammation and the ischemic stroke measuring the levels of IL-6 in the blood of acute ischemic stroke patients. Plasma IL-6 was measured in 46 patients in the first 24 hours after acute ischemic stroke and in 98 controls matched for sex and age. Forty-five out of 46 acute ischemic stroke patients presented high IL-6 values. Fourteen out of 98 controls presented IL-6 values higher than normal. Mean level of circulating IL-6 was in acute ischemic stroke patients 26.5 +/- 2.3 pg/mL (range 6.4-161.3 pg/mL), significantly higher as compared to that in controls 3.9 +/- 1.5 pg/mL (range 2.3-5.9 pg/mL) [p < 0.0001, 95% CI (9.186 to 457.53)]. In our study, IL-6 levels were significantly elevated in the first 24 hours after ischemic stroke. This observation supports the hypothesis that IL-6 production is an inflammatory response to acute hypoxic-ischemic injury. IL-6 may serve as warning sign, because it increases early in inflammation.

An immunological approach to cerebral ischemia (I). Immune cells and adhesion molecules.

Ischemic stoke is a major cause of death and an important source of disability in industrialized countries. Since there is no ideal treatment for cerebral ischemia, any approach aiming to limit the devastating consequences of the ischemic process is justified. Concerning immune responses, it has become clear in the latest years that actors of the immune system are involved in multiple and various neurobiological processes such as cerebral ischemia, neurodegeneration, neuroprotection and neuroregeneration. An immunological approach to cerebral ischemia can distinguish, besides the implication of inflammation in the developing of atherothrombosis thus leading to stroke, the clear involvement of immune cells and mediators in processes continuing the initial stage of ischemia, having consequences on recovery or lesion extent. Cerebral infarctions develop within minutes to hours of cessation of the cerebral blood flow, but may expand over subsequent days. There is increasing evidence that leukocytes, cytokines, cell adhesion molecules, and other immune mediators contribute to secondary infarction growth, but inflammatory cytokines are also involved in signaling pathways leading to neuroprotection related to ischemic pre-conditioning. The aim of this review is to show some aspects concerning the complex and diverse functions of immune modifications occurring in cerebral ischemia. This first part will focus on the involvement of immune cells, adhesion molecules and immunological transcription factors in the development of ischemic lesion.

Some clinico-immunological aspects in patients with ocular myasthenia gravis associated with inflammatory bowel disease.

The link between inflammatory bowel disease (IBD) and ocular myasthenia gravis (OMG) is thought to be related to the production of autoantibodies. The aim of this study was to determine the incidence of some antibodies in OMG patients with IBD. Sixty-four patients with IBD and neurological symptoms were examined neurologically and immunologically (41 men and 23 women, mean age 43-5.4 years); mean duration of IBD before the diagnosis of OMG was 7.5 years. The following immunological investigations were performed: anti-acetylcholine receptor antibodies (AChR Abs) (ELISA), anti-smooth muscle antibodies (ASMA) (indirect immunofluorescence), perinuclear anti-neutrophilic cytoplasmic antibodies (p-ANCA) (indirect immunofluorescence), carcinoembryonic antigen (CEA) (ELISA), Saccharomyces cerevisiae antibodies IgA and IgG (ASCA) (ELISA), peripheral lymphocyte counts, immature CD4, CD4/CD8 ratio. Five patients out of 64 with IBD presented OMG. The following antibodies were observed: anti-AChR in 4 OMG patients, ASMA in 4 OMG patients, p-ANCA in 4 OMG patients, CEA in 5 OMG patients, ASCA IgA and IgG in 3 OMG patients. Of 5 OMG patients 4 were positive for >3 antibodies. The peripheral lymphocytic counts were reduced in 5 OMG patients, a decline in CD8 cells and an increase in immature CD4 cells in 5 OMG patients, an increased CD4/CD8 ratio in 5 OMG patients were observed. The association of IBD with OMG was rare. Autoimmune dysregulation is the central defect in both MG and IBD. Further studies are required to define the nature of this association.

Ischemic stroke accompanied by anti-PR3 antibody-related cerebral vasculitis and hepatitis C virus infection.

BACKGROUND: Hepatitis C virus (HCV) infection has been found to be strikingly associated with autoimmune phenomena. Autoantibodies are commonly found in patients with HCV infection. PURPOSE: The aim of the present study was to investigate the presence of anti-neutrophil cytoplasmic antibody (ANCA) in patients with ischemic stroke and HCV infection. MATERIAL AND METHODS: ANCA were determined in sera from 36 patients with ischemic stroke and HCV infection (18 females, 18 males, mean age 75+/-10 years) and 44 healthy controls. Assays employed were indirect immunofluorescence for detection of ANCA and ELISA for anti-proteinase 3 (anti-PR3-ANCA). No one of the patients studied received IFN-alpha treatment before blood collection. RESULTS: ANCA were positive in 21 out of 36 (58 %) patients with ischemic stroke and HCV infection. All sera with ANCA showed cANCA patterns and contained anti-PR3 specificity. HCV patients with ANCA showed a higher prevalence of cerebral vasculitis. CONCLUSION: HCV may be regarded as a possible causative factor in ANCA-related vasculitis.

Evaluation of antiphospholipid antibodies in young women with ischemic stroke.

There is an association between antiphospholipid antibodies (aPL) and ischemic stroke. The detection of aPL in young women is to characterize a subset of patients with venous or/and arterial thrombotic complications, to describe whether aPL are a cause, a consequence, or an accompanying event. Cerebral ischemia is the most common arterial thrombotic manifestation associated with the presence of aPL. In patients with ischemic stroke, diagnostic value of aPL can be increased by patient testing for antibodies against cardiolipin. The aim of the study was to assess the prevalence of IgG-aCL in young women with ischemic stroke. IgG-aCL were screened by ELISA in 34 young women, under the age of 45 (mean age 36.7 years) with ischemic stroke without the common stroke risk factors: hypertension, diabetes, hyperlipidemia, vasculitis or arterial fibrillation, smoking. Other 20 healthy, age and sex matched adults with no evidence of disease were also included as a control group. Twelve of the 34 (35%) patients were found to have aCL of the IgG isotype. The present study confirmed that IgG-aCL may be associated with ischemic stroke; this phenomenon is however relevant only in a small subgroup of young women. They should be sought in all stroke patients under the age of 45, especially those with previous histories of deep venous thrombosis, spontaneous abortion or thrombocytopenia.

Investigation of TNF-alpha, IL-6, IL-8 and of procalcitonin in patients with neurologic complications in sepsis.

Some mediators of inflammation are associated with sepsis, involving nervous system. Proinflammatory cytokines, TNF-alpha, IL-6, and IL-8, and procalcitonin (PCT), proinflammatory protein, were investigated in patients with neurologic complications in sepsis. TNF-alpha, IL-6, IL-8, and PCT were prospectively investigated in 62 patients with neurologic complications in sepsis. TNF-alpha and IL-6 were studied both in serum as in the CSF, IL-8 and PCT were studied only in serum. TNF-alpha, IL-6, and IL-8 were studied by ELISA (R & D Systems), and the PCT by immunoluminometric assay (BRAHMS). Mean value of TNF-alpha in serum was 578+/-214 pg/ml, and in CSF was 458+/-167 pg/ml (p<0.01). Mean value of IL-6 in serum was 749+/-213 pg/ml, and in CSF was 617.5+/-182 pg/ml (p<0.01). Mean value of IL-8 in serum was 332+/-196 pg/ml (p<0.01). Mean value of PCT in serum was 80+/-16 ng/ml (p<0.01). The investigated parameters do not permit the identifying of cases with neurologic complications. The increased correlation coefficient between cytokines in serum and in CSF suggests the damage of the blood-brain barrier. The raise of PCT in serum, induced by TNF-alpha and IL-6, is an argument of the severity of sepsis.