Solveig Klæbo Reitan

Immunoglobulin heavy chain constant regions regulate immunity and tolerance to idiotypes of antibody variable regions

Particular syngeneic adjuvant-free monoclonal antibodies are immunogenic and elicit antibody responses against the variable region idiotypes (Ids). We here study how heavy-chain constant regions (CH) regulate immune responses to Ids of free, uncomplexed monoclonal antibodies. To this end, we selected two hybridomas, called Id3 and IdA.01, that produce immunogenic IgMλ2 directed toward 2,4,6-trinitrophenyl, and subcloned rare IgG1, IgG3, IgE, or IgA class switch variants. The purified switch variants, which possessed the Ids of their IgM progenitors, were injected repeatedly without added adjuvant into BALB/c mice, and anti-Id IgG responses were determined. These repeated injections revealed that the immunogenicity of Ids was lost by switching to IgG1 and IgG3, restored when the Fc piece of IgG1 was removed, maintained by switching to IgE and monomeric IgA, and lost in polymeric IgA. Loss of immunogenicity was associated with acquisition of Id-specific tolerogenicity, as determined by immunization challenge with Id borne by IgM. An Id borne by IgG induced tolerance when injected at least 90 days before or 3–21 days after immunization with IgM Id was begun. Ids of IgG were also tolerogenic in mice deficient in FcγRIIB or FcγRI + III. The results suggest that Ids that have switched to IgG and pIgA negatively control immune responses to shared Ids, including the Ids of their IgM progenitors.

The primary IgM antibody repertoire: a source of potent idiotype immunogens

A widely held view is that, to elicit adaptive immune responses, most protein antigens must be given with adjuvants that activate the innate immune system. It has also been proposed that the immune system is tolerant to idiotypes (Id) of the syngeneic primary antibody (Ab) repertoire. We now show that among 73 purified noncomplexed secretory IgM monoclonal antibodies (mAb), 4 (5.5%) elicited high levels of IgG Ab against the Id even though no adjuvant was added. The responses were controlled by H2‐linked immune response genes. IgG1, but no IgG2a or IgG2b, anti‐Id Ab were detected, indicating involvement of T helper type 2 (Th2) cells. All 4 IgM mAb are likely germ‐line gene‐encoded, and 1 was shown to represent a recurrent Id. After endotoxin depletion the most potent immunogen of the 4 still provoked robust humoral anti‐Id responses. The results suggest that a natural protein of the primary IgM Ab repertoire can be immunogenic without an adjuvant.

Depression has a Strong Relationship to Alterations in the Immune, Endocrine and Neural System

Epidemiological findings indicate a connection between depressive symptoms and changes in status of the immune system in depressed patients. This raises the possibility of causative connections. Theories on mechanisms for interactions between immune and affective systems – directly and via endocrine system – are evolving. Such hypothesized causative connections are supported by several findings. First, in depressed patients changes in the status of the immune system in vivo and ex vivo are seen. Also, depressive symptoms are seen in patients with altered immune status (physiologically, pathologically or chemically induced). Knowledge in this field may have implications regarding psychiatric follow up of physically ill people suffering from diseases caused by an altered immune system (long lasting infections, autoimmune diseases, hypersensitivity disorders) as well as disorders for which treatment and prognoses depends on the immune system (infections, cancer). Similarly, medical treatment of depressed patients may be adjusted by more specific knowledge about the interaction between neuroimmunology and depression. Important findings and the present knowledge and theories are reviewed.

Prevalence of serum anti-neuronal autoantibodies in patients admitted to acute psychiatric care.

BACKGROUND Autoimmune encephalitis associated with anti-neuronal antibodies may be challenging to distinguish from primary psychiatric disorders. The significance of anti-neuronal antibodies in psychiatric patients without clear evidence of autoimmune encephalitis is unknown. We investigated the serum prevalence of six anti-neuronal autoantibodies in a cohort of unselected patients admitted to acute psychiatric care. METHOD Serum was drawn from 925 patients admitted to acute psychiatric in-patient care. Psychiatric diagnoses were set according to International Classification of Diseases (ICD)-10 criteria. Antibody analysis was performed with an indirect immunofluorescence test for N-methyl d-aspartate receptor (NMDAR) antibodies and five other anti-neuronal autoantibodies of the immunoglobulin (Ig) classes IgA, IgG and IgM isotype. RESULTS Anti-neuronal autoantibodies were found in 11.6% of patients: NMDAR antibodies in 7.6%, contactin-associated protein-like 2 (CASPR2) antibodies in 2.5%, glutamic acid decarboxylase-65 (GAD65) antibodies in 1.9%, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antibodies in 0.1%. Leucine-rich glioma-inactivated protein-1 (LGI1) and γ-aminobutyric acid B (GABAB) receptor antibodies were not detected. NMDAR antibodies of class IgG were present in five patients only (0.5%). NMDAR antibodies of all Ig classes were equally prevalent in patients with and without psychosis. There were no significant differences in antibody prevalence in the different diagnostic categories, except for a higher odds ratio of being NMDAR antibody positive for patients without a specific psychiatric diagnosis. CONCLUSIONS NMDAR IgG autoantibodies, which are known to be strongly associated with anti-NMDAR encephalitis, were rarely found. CASPR2 and GAD65 antibodies were more frequently encountered in the present study than previously reported. Further research on the clinical significance of anti-neuronal autoantibodies in patients with acute psychiatric symptoms is needed.

Association of psychosis, affective disorders and diseases affecting the immune system

Abstract Purpose of the article: There are indications of altered immune activity in depressed and psychotic patients compared to healthy controls in several studies. To explore the clinical importance of this phenomenon we examined the relation between different disorders affecting the immune system and psychoses and depression, respectively. Materials and methods: A total of 276 patients consecutively admitted to a psychiatric acute ward were included in the study. Of these 41 patients fulfilled the criteria for ICD-10 F20–29 (psychotic) diagnosis and 157 patients a F30–39 (affective) diagnosis. Information on diseases affecting the immune system in patients themselves and family members of the patients were obtained by a self-report questionnaire. Results: Comparing the two groups showed a significant correlation between the F20–29 group and eczema (r = −0.116, p = .037). Comparing what patients reported for family members showed a significantly higher frequency of epilepsy (p = .033) in the F20–29 group. Summarizing all immunological diseases for family members showed a significantly higher frequency in the F30–39 group compared to the F20–29 group (χ2 = 4, 82, df = 1, p = .028). Conclusions: There may be differences between the F20–29 and F30–39 groups and their family members regarding risk for diseases affecting the immune system. This is in line with different activity of the immune system measured in blood for the disorders and may add information regarding etiology and pathology of these psychiatric diseases. Further studies including a greater number of subjects, as well as confirmation of the immunological diseases through blood samples are needed.

Onconeural Antibodies in Acute Psychiatric Inpatient Care

Paraneoplastic neurological disorders associated with onconeural antibodies often appear with neuropsychiatric symptoms. To study the prevalence of onconeural antibodies in patients admitted to acute psychiatric inpatient care, the serum of 585 such patients was tested for antibodies targeting MOG, GLRA1B, DPPX, GRM1, GRM5, DNER, Yo, ZIC4, GAD67, amphiphysin, CV2, Hu, Ri, Ma2, and recoverin. Only one sample was positive (antirecoverin IgG). The present findings suggest that serum onconeural antibody positivity is rare among patients acutely admitted for inpatient psychiatric care. The clinical implications of this finding are discussed.

Association between cytokines and psychiatric symptoms in chronic fatigue syndrome and healthy controls

Abstract Purpose: The reports regarding the status of the immune system in patients with chronic fatigue syndrome/myalgic encephalopathy (CFS/ME) have been inconclusive. We approached this question by comparing a strictly defined group of CFS/ME outpatients to healthy control individuals, and thereafter studied cytokines in subgroups with various psychiatric symptoms. Materials and methods: Twenty patients diagnosed with CFS/ME according to the Fukuda criteria and 20 age- and sex-matched healthy controls were enrolled in the study. Plasma was analysed by ELISA for levels of the cytokines TNF-α, IL-4, IL-6 and IL-10. Participants also answered questionnaires regarding health in general, and psychiatric symptoms in detail. Results: Increased plasma levels of TNF-α in CFS/ME patients almost reached significance compared to healthy controls (p = .056). When studying the CFS/ME and control groups separately, there was a significant correlation between TNF-α and The Hospital Anxiety and Depression Scale (HADS) depressive symptoms in controls only, not in the CFS/ME group. A correlation between IL-10 and psychoticism was found in both groups, whereas the correlation for somatisation was seen only in the CFS/ME group. When looking at the total population, there was a significant correlation between TNF-α and both the HADS depressive symptoms and the SCL-90-R cluster somatisation. Also, there was a significant association between IL-10 and the SCL-90-R cluster somatisation when analyzing the cohort (patients and controls together). Conclusions: These findings indicate that immune activity in CFS/ME patients deviates from that of healthy controls, which implies potential pathogenic mechanisms and possible therapeutic approaches to CFS/ME. More comprehensive studies should be carried out on defined CFS/ME subgroups.

Use of mechanical and pharmacological restraint over an eight-year period and its relation to clinical factors

Abstract Background: Use of restraint and finding the balance between security and ethics is a continuous dilemma in clinical psychiatry. In daily clinic and in planning health-care service, knowledge on the characteristics of restraint situations is necessary to optimize its use and avoid abuse. Methods: We describe characteristics in the use of pharmacological and mechanical restraint in psychiatric acute wards in a hospital in Middle Norway over an eight-year period. Data on all cases of mechanical and pharmacological restraint from 2004 to 2011 were retrospectively collected from hand-written protocols. Complementary information on the patients was obtained from the hospital patient administrative system. Results: Restraint in acute wards was used on 13 persons per 100,000 inhabitants annually. The percentage of admitted patients exposed to restraint was 1.7%, with a mean of 4.5 cases per exposed patient. Frequency per 100 admitted patients varied from 3.7 (in 2007) to 10 (in 2009). The majority of restraint cases concerned male patients under 50 years and with substance-abuse, psychotic, or affective disorders. Significantly more coercive means were used during daytime compared to night and morning. There was a significant increase in pharmacological coercion during spring and mechanical coercion during summer. Conclusions: Restraint was used on 1.7% of admitted patients, representing 13 per 100,000 inhabitants per year. Use of restraint was higher during certain periods of the day and was associated with the patient’s diagnosis, age, gender, and legal status of hospitalization. There was a marked variation over the years.