Increased α-Defensins as a Blood Marker for Schizophrenia Susceptibility

Abstract

Schizophrenia is a severe psychotic illness affecting 1% of the general population. There are no consistent pathological features, and the disorder is defined by a complex symptomatology, which overlaps with other psychiatric illnesses. Diagnosis is based on a clinical interview, relying on the patient meeting criteria according to diagnosis manuals, including Diagnostic and Statistical Manual of Mental Disorders, 4th Ed. and International Statistical Classification of Diseases, 10th Revision. Because of the ambiguous symptoms, the diagnostic process can take many months and often years. Rapid and effective treatment has been shown to impact positively on disease progression and outcome, and it is therefore important to identify disease-associated biomarkers allowing early diagnosis. Reliable biomarkers can be used for the development of diagnostic tests and may also help us understand the underlying pathology of this disorder. In the present study, proteins from anti-CD3 stimulated and unstimulated peripheral blood T cell lysates from 15 minimally medicated and unmedicated patients and 15 age-, sex-, race-, and smoking-matched controls were profiled on cation exchange (CM10) chips using SELDI-TOF. Partial least squares discriminate analysis was used to separate patient and control groups according to the expression of 108 detected peaks, and two peaks of 3,374 and 3,450 Da, corresponding to ␣-defensins based on masses and cationic properties, were found to contribute significantly to the separation of patient and control groups. Reduction of T cell lysates with DTT resulted in a 6-Da shift in the mass of these peaks consistent with the presence of three cysteine bonds in the structure, confirming them as ␣-defensins. Quantification of ␣-defensins in T cell lysates from six patients and 18 healthy controls was carried out by ELISA, which also showed that ␣-defensin levels were significantly increased in patient lysates when com- Schizophrenia is worldwide one of the most severe psychiatric disorders with a prevalence of 1% in the general population. The causes of this devastating disorder are still undetermined, although schizophrenia is widely believed to have a multifactorial etiology with contribution from both heritable and environmental factors. Despite decades of research, we have failed to find consistent pathological features across cases, making laboratory-based diagnosis impossible at the present time. Among the most widely reported findings in schizophrenia are decreased cerebral volume with ventricular enlargement (for a review, see Ref. 1) and a greater prevalence of neurological soft signs (2) as well as hypofrontality (3). There is robust evidence to support a heritable risk to the development of schizophrenia, and individuals with an affected relative have an increased chance of developing schizophrenia. The risk increases with the closeness of the relative but only reaches ϳ50% concordance in monozygotic twins (4), suggesting that environmental risk factors play an important role. Patterns of in...

Biomarkers in schizophrenia: A focus on blood based diagnostics and theranostics

“…In psychiatry, such studies have involved the use of whole blood [129131] , lymphocytes [132] or PBMC samples [133135] to identify potential biomarkers for Sz. Other studies examined proteomics information in RBC [109] , T cells [136] , and serum [61,109,137,138] in attempts to answer the same question. This approach has typically led to a large set of mRNAs or proteins being proposed as possible biomarkers in Sz but most findings await replication.…”

“…Taken together, there is only downregulation of intercellular adhesion molecule in people with Sz that were replicated in at least two microarray studies [138,140] . Other studies have identified markers that may be of use in identifying people who are at risk of developing the disorder, such as the up-regulation of DEFA in T cells and plasma from people with Sz, and both their affected or unaffected monozygotic twin [136] . Of interest is the downregulation of apolipoprotein A1 identified in both red blood cells of people with Sz and serum of people with Sz who were drugnaive [109] .…”

Peripheral Biomarker Candidates in Schizophrenia

“…Furthermore, the results of a twin-based study suggest that antimicrobial peptides (α-defensins) might be early markers for the risk of developing schizophrenic symptoms later in life [37]. Another study found that the acute-phase proteins C3 and C4 as well as ceruloplasmin, which interestingly also possess antimicrobial properties, correlate with negative symptoms in acute paranoid schizophrenia [38].…”

Markers of Blood Cell Activation and Complement Activation in Factor VIII and von Willebrand Factor Concentrates

“…We have shown that human a-defensins can induce platelet activation [21]. An increased level of a-defensins was shown to be a blood marker for schizophrenia susceptibility [22]. These peptides have also been described as early markers for the development of colorectal adenomas and carcinomas, and it has been suggested that they might contribute to tumor growth [23].…”