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.

New Insights into Antisynthetase Syndrome.

Antisynthetase syndrome (ASS) is a rare chronic autoimmune disorder (2-3 times more common in women than in men), associated with interstitial lung disease (the most important feature), dermatomyositis (DM), and polymyositis (PM). The cause of ASS is unknown. Recent developments in immunology have improved our knowledge and it is now possible to classify ASS according to the presence of myositis specific autoantibodies. The hallmark of ASS is the presence of serum autoantibodies directed against aminoacyl-tRNA synthetases (anti-ARS involved in protein synthesis). ASS is due to IgG antibodies directed against the enzyme synthase. Antisynthetase antibodies (ASAb) include: anti-histidyl- (anti-Jo-1, being the best known), anti-threonyl- (anti-PL-7), anti-alanyl (anti-PL-12), anti-isoleucyl- (anti-OJ), anti-glycyl- (anti-EJ), anti-asparaginyl- (anti-KS), anti-Wa, anti-tyrosil- (anti-YRS), anti-phenylalanyl-transfer RNA synthetase (anti-Zo), and anti-signal recognition particle (anti-SRP). Anti-Jo-1 is the most common ASAb (in ~20-30% of PM/DM patients).

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.

Multiple Intracerebral Hemorrhages in an Old Patient with Rheumatoid Arthritis.

A 78-year-old Caucasian man was admitted in the Department of Neurology for visual disturbances, started two days before. The next day the patient experienced headache, fever and gait disturbances. He had hypertension, diabetes mellitus, an ischemic stroke 13 years ago, longstanding seronegative rheumatoid arthritis (17 years), polynodular goiter, right ischio-pubian fracture and right femoral vein thrombosis a year ago due to a car accident, since he is treated with oral anticoagulants associated to antiaggregant, hypotensors, statin and oral antidiabetics. The neurologic examination had evidenced nuchal rigidity, left homonymous hemianopsia, left central facial palsy, ataxia of the inferior limbs with wide-based gait, achilean reflexes abolished bilaterally, bilaterally abolished plantar reflexes, ideomotor apraxia, dysarthria, hypoprosexia, and preserved consciousness patient. A non-contrast cerebral CT scan had shown right temporal and parieto-occipital intraparenchymatous hemorrhages, a right frontal sequelar lesion, multiple old lacunar infarets, cortical atrophy. Laboratory findings included an inflammatory syndrome, absence of rheumatoid arthritis positive serology, normal coagulogram, an elevated proteinuria. The cerebral IRM performed on the seventh day of hospitalisation was suggestive for subacute right parietal hemorrhage, old cerebral infarction in the right anterior cerebral artery area, old lacunar infarcts and cerebral atrophy. The anticoagulant and antiaggregant treatment was stopped after a generalized tonic-clonic seizure occurred. Antiedematous, hypotensor, anticonvulsivant, beta-blocker, and symptomatic treatment was started, while the antidiabetic treatment was continued. All symptoms remitted. Arguments for amyloid angiopathy in our patient are previous non-cardioembolic ischemic stroke and a chronic inflammatory disease- rheumatoid arthritis in his personal medical history.

Ischemic strokes in a young patient with dermatomyositis, systemic lupus erythematosus and secondary antiphospholipid syndrome mimicking herpetic encephalitis.

A 44-year-old right-handed Caucasian male was initialy diagnosed in 2007 with dermatomyositis (DM) and in 2009 with systemic lupus erythematosus (SLE) (overlap syndrome). He was treated with Methylprednisolone and Hydroxychloroquine. He interrupted the treatment in the last three years. The patient presented with fever (39.8 degrees C), left zoster ophthalmicus, headache and psychomotor agitation. The cerebral CT scan showed left hemispheric hypodense lesions. Herpetic encephalitis was suspected. The patient was referred to the Institute of Infectious Diseases. The patient's neurological status worsened, he presented spastic tetraparesis and aphasia. DW-MRI, ADC, DS and AngioMRI were done, the patient proved to have an ischemic stroke due to acute thrombosis of the left internal carotid artery and multiple watershed infarctions. An infectious pathology, including HSV-1, was excluded by PLEX ID performed from CSF. Acyclovir, anti vitamin K, steroidal intravenous pulse therapy was started. The patient was referred after two weeks to the Department of Neurology. Mild inflammatory syndrome, tests for anti-double stain DNA (dsDNA), anti-Sm, anti-SSA, IgM and IgG anti-cardiolipin antibodies and lupus anticoagulant were positive. He was currently treated with Methylprednisolone (48 mg/d), anti vitamin K, statin, symptomatics. The outcome was favorable, with good laboratory response. Overlap syndrome may be associated with a significant increase in the risk of stroke. Our case presented without clinically susceptible symptoms of stroke but found to have stroke after neurological assessment associated with overlap syndrome (DM and SLE).

Troponin T changes in acute ischemic stroke.

Elevation of cardiac troponin T (cTnT) in serum reflects myocardial injury, but it was also observed in other conditions with cardiac injury including acute ischemic stroke. The objective was to identify the relationship between elevated cTnT and stroke severity, location and outcome, cTnT levels were prospectively performed in 385 patients with different subtypes of acute ischemic stroke admitted in NICU within 72 hours of onset, as TOAST criteria. The patients were divided into two groups: an elevated cTnT (group 1) (n = 42) and a normal cTnT (group 2) (n = 343). The short-term prognosis was assessed by 30-days modified Rankin Scale responder analysis and the NIHSS. Serum cTnT levels were determined using a high sensitive troponin T assay (Roche Elecsys Troponin, Mannheim, Germany), cut-off value of 0.01 ng/ml. Statistical analysis was performed. Serum cTnT level was elevated in 10.91% (42/385) of patients, cTnT positivity on admission is an independent and powerful prognosis predictor in acute ischemic stroke. It was observed a more frequent insular lobe involvement in elevated cTnT group (17/42) (31%) than in group 2 (55/343) (16%) (p = 0.040). Stroke severity was greater in elevated cTnT group. The outcome was worse in elevated cTnT group as compared to group 2 (13/43) (30.95%) vs. (68/343) (19.82%) (p = 0.013). cTnT in acute ischemic stroke is a marker of stroke severity, of insular lobe lesion and of prognosis prediction. cTnT is a highly specific and sensitive marker of myocardial damage in acute ischemic stroke due to insular lesion that induces disturbances of autonomic balance.

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.

Peripheral nervous system manifestations in systemic autoimmune diseases.

The peripheral nervous system refers to parts of the nervous system outside the brain and spinal cord. Systemic autoimmune diseases can affect both the central and peripheral nervous systems in a myriad of ways and through a heterogeneous number of mechanisms leading to many different clinical manifestations. As a result, neurological complications of these disorders can result in significant morbidity and mortality. The most common complication of peripheral nervous system (PNS) involvement is peripheral neuropathy, with symptoms of numbness, sensory paresthesias, weakness, or gait imbalance. The neuropathy may be multifocal and asymmetric or, less frequently, distal and symmetric.

Rheumatoid arthritis and ischemic strokes in a young woman. Are these conditions interrelated?

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease which is associated with an increased risk of cardio and cerebrovascular pathology. A 48-year old Caucasian female was admitted for diffuse arthralgias. She was diagnosed eight years before with seropositive RA and she received Methotrexate, Prednisone and anti-inflammatory drugs. A week after the admission the patient presented sudden onset of left hemiplegia. Cerebral CT scan was suggestive for acute infarction in the right middle cerebral artery area and an old sequelar infarction in the left posterior artery area. Laboratory tests revealed: erythrocyte sedimentation rate of 40 mm/hour, fibrinogen 656 mg/dL, C-reactive protein of 20 mg/dL, rheumatoid factor 66.83 U/mL, anti CCP3 IgG 213.54 U/mL, ANA 128.126 U/mL. Also, she had high LDL-cholesterol serum concentration (190 mg/dL). The ECG revealed sinus rhythm, QRS axis-45 degrees, antero-lateral ischemia. Ultrasound examination of cervico-cerebral arteries emphasized occlusion of the left internal carotid artery, large atheromas in both carotid and vertebral arteries. A treatment with anti-aggregant and statin was started, and the former treatment for RA was continued with a raised Prednisone dose. The outcome was favorable, the patient's motor deficit improved (3/5 BMRC at the upper limb and 4/5 at the inferior limb) and she was able to walk with a cane support. She also presented an alleviation in the laboratory test status. Ischemic stroke is a possible complication of RA, presenting as principal risk factor precocious atherosclerosis. A better control of inflammation by new anti-rheumatic treatments will protect the RA patients of deleterious effects of ischemic stroke.

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.

Investigation of inflammatory activity in ulcerative colitis.

Inflammatory bowel diseases (IBDs), ulcerative colitis and Crohn's disease are lifelong disorders, characterized by the chronic inflammation of all or part of our digestive tract. Cytokines have an essential role in the pathogenesis of IBDs, because they control the inflammatory response, and the disequilibrium of pro-inflammatory/anti-inflammatory cytokines may lead directly to tissue destruction. Histopathologically, these diseases are characterized by the extent and the distribution of mucosal architectural abnormality, the cellularity of the lamina propria and the present cell types, but these features frequently overlap. We performed a prospective study, which included 46 patients diagnosed with ulcerative colitis (UC) (gender ratio 25 males/21 females, mean age 44.8 years) and 30 subjects, with similar demographic characteristics, which were selected from the patients investigated for other digestive disorders, unaffected by UC. Serological investigations were performed by quantitative determination of IL-17, IL-13, and CRP using ELISA sandwich technique. We have achieved significantly higher concentrations of IL-13, IL-17 and CRP in the serum of patients with UC, compared to the control group. We have found in our study correlations between ulcerative colitis activity and serum levels of interleukins, IL-13 and IL-17. Because IL-17 serum levels were significantly correlated with the disease severity and only cytokine had a significantly statistic correlation with high serum levels of CRP in UC patients, IL-17 can be considered an important progress inflammation marker of this disease.

Evaluation of oxidative stress in patients with acute ischemic stroke.

Oxidative stress is involved in the pathogenesis of acute ischemic stroke. Antioxidants are consumed in the reaction with free radicals generated during the oxidative stress. The aim of the study was the to evaluate the oxidative stress in patients with acute ischemic stroke. Malondialdehyde (MDA), plasma glutathione, plasma glutathione peroxidase (GPX), catalase (CAT), uric acid, bilirubin, plasma superoxide dismutase (SOD), red blood cells superoxide dismutase (RBS SOD) (spectrophotometric assay), total antioxidant capacity (TAC) (enhanced chemiluminescence), ceruloplasmin, C-reactive protein (CRP), albumin, transferrin (nephelometric assay) were performed in 57 patients (mean age 73.4 +/- 6.5 years) with acute ischemic stroke within 24 hours and at 7 days after stroke onset as compared to 51 age-and sex-matched controls. Significantly lower values in the first 24 hours were: plasma glutathione, CAT, plasma SOD, RBS SOD (p < 0.001), plasma GPX, TAC, transferrin (p < 0.05). Significantly higher values in the first 24 hours were: CRP (p < 0.001), MDA, uric acid (p < 0.05). Significantly lower values at 7 days were: TAC, albumin, transferrin (p < 0.001), plasma glutathione, plasma SOD, CAT (p < 0.05). Significantly higher values at 7 days were: MDA, plasma GPX, RBC SOD, CRP, uric acid, bilirubin (p < 0.001), ceruloplasmin (p < 0.05). These results indicate that oxidative stress is increased and that the majority of antioxidants are reduced; this suggests the possibility of therapeutic intervention with antioxidant agents.

Role of leptin in autoimmune diseases.

Leptin represents a link between metabolism, nutritional status, and immune responses. Leptin is important for optimal functioning of the immune system. Leptin is a cytokine-like hormone with proinflammatory properties linked to autoimmune diseases. Moreover, there has been increasing evidence that leptin is involved in the pathogenesis of various autoimmune diseases. Leptin has been shown to enhance immune reactions in autoimmune diseases that are commonly associated with inflammatory responses. Both high and low levels of leptin might contribute to autoimmune diseases. Leptin has been explored as a potential target for therapeutic development in treating autoimmune diseases. In this review, we review here the most recent advances on the role of leptin in autoimmunity and in immune-rheumatological diseases.

Liver involvement in patients with systemic autoimmune diseases.

ABSTRACT: A wide variety of systemic autoimmune diseases (SAD) affects the liver, and various forms of hepatic involvement have been reported. Patients who have SAD, the abnormal liver function tests might be caused by SAD. In most of these patients, SAD should be treated primary. Liver involvement in SAD is a matter of great clinical challenge evoking several questions upon diagnostic criteria for liver diseases and the presence of overlap syndromes. This review will describe liver injury caused by various systemic autoimmune diseases.

Could pro-BNP, uric acid, bilirubin, albumin and transferrin be used in making the distinction between stroke subtypes?

To establish the pathogenesis of ischemic strokes is very important in determining an adequate therapy. The objective was to observe if certain plasma parameters could be used as biomarkers in distinguishing between stroke subtypes. Plasma pro-BNP (chemiluminescence), serum uric acid, bilirubin (colorimetric assay), albumin and transferrin (nephelometric assay) levels were performed in 168 admitted patients (mean age 68.7 +/- 11.6 years, 52 men and 116 women) with different subtypes of acute ischemic strokes within 24 hours and at 7 days after stroke onset as TOAST and OCSP criteria, NIHSS and Glasgow Coma Score at baseline and at 7 days were used. The mean value of pro-BNP level was significantly higher in the cardioembolic stroke (CE), in patients, within 24 hours (p < 0.001) and at 7 days (p < 0.001) after stroke onset. A negative correlation between pro-BNP levels and GCS (r = 0.05, p < 0.0002) and a significant difference between pro-BNP levels of NIHSS groups were observed (p < 0.08, respectively (p < 0.01). We observed significantly higher values within 24 hours of uric acid (p < 0.05), significantly lower values within 24 hours of transferrin (p < 0.05), significantly lower values at 7 days of albumin and transferrin (p < 0.001), significantly higher values at 7 days of uric acid and bilirubin (p < 0.001). No significant statistical differences between the values of oxidative stress parameters and stroke subtypes, GCS and NIHSS score were observed. The level of plasma pro-BNP may be useful in distinguishing CE stroke from other stroke subtypes. Oxidative stress is increased in acute ischemic stroke, but oxidative stress parameters could not be used to differentiate stroke subtypes.

Acute intermittent porphyria--diagnostic and treatment traps.

Acute intermittent porphyria (AIP) is a rare metabolic disease defined by mutations coding the deaminaze enzyme of porphobilinogen (PBGD). Porphyrias are somewhat misdiagnosed as a consequence of light symptoms in patients. Acute forms of porphyria can be life-threatening, so a correct diagnosis and an accurate treatment are highly important. The authors presented the case of a 38-years-old patient admitted for persistent abdominal pain that previously presented two generalized convulsive seizures. The diagnosis of AIP was established by the raised concentration of urinary porphyrins. Despite treatment with carbohydrates and hemines, the clinical picture of the patient worsened, with tetraplegia and severe respiratory failure. The patient died seven weeks after the initial presentation of the disease.

Metabolic syndrome in rheumatoid arthritis.

Rheumatoid arthritis (RA) generally affects people between the ages of 20 and 50. Patients with RA have a significantly higher prevalence of the metabolic syndrome (MS) compared to the general population. The increased cardiovascular risk (CVR) associated with RA places this disease among the most widely studied. The duration of RA was associated with MS, implicating the role of inflammation in MS development. The presence of MS correlates with increased subclinical atherosclerosis. A positive correlation between prevalence of MS and worsening of functional status was found in patients with RA. Patients with rheumatoid arthritis have an increased risk and a higher mortality from cardiovascular diseases (CVD), the rheumatologist should be aware of those MS risk factors and attempt to modify them. This review summarizes recent advances in the field of MS in RA.

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.

Associated pulmonary arterial hypertension in connective tissue diseases.

In recent years, major advances have been achieved in the understanding of pulmonary arterial hypertension (PAH) patho-physiology. Associated pulmonary arterial hypertension (APAH) can occur in a variety of other conditions and circumstances including a number of systemic autoimmune diseases. As with PAH in general, clinical symptoms of APAH in systemic autoimmune diseases are unspecific. In addition, there is a long standing association between autoimmunity and APAH. It has been postulated that autoimmunity may play a role in the pathogenesis of APAH. This argument has been based on frequent coexisting clinical and serological rheumatic findings. There is no experimental model of immune mechanism-dependent severe APAH. The loss of self-tolerance could initiate a process which ultimately results in APAH. It is possible that T-cell deficiencies (in either function or number) may contribute to pulmonary vascular injury or disease. These conditions are often associated with autoantibodies as well as defects in the CD4 T-cell compartiment. However, it remains uncertain how autoimmune mechanisms contribute to the pathogenesis of APAH. There are data that show a significant association between APAH and connective tissue diseases (CTD). In this regard, systemic sclerosis, mixed connective tissue disease, systemic lupus erythematosus, dermato/polymyositis and primary Sjögren's syndrome are associated with APAH. The study of APAH in the systemic autoimmune diseases and its relation to basic immunologic disturbances may yet bring effective therapies in the future. APAH can be a severe complication attracting a high excess mortality in autoimmune diseases. The present review will focus on what is known about autoimmune phenomena in APAH patients.