Naturally Occurring Antibodies Against Bim Are Decreased in Alzheimer’s Disease and Attenuate Ad-type Pathologies in a Mouse Model

Background Alzheimer’s disease (AD) is the most popular neurodegenerative disease affecting cognitive functions of the elderly population. Neuronal apoptosis is an important pathological process during the development of AD. The Bcl-2-interacting mediator of cell death (Bim) mediates Amyloid-beta (Aβ)-induced neuronal apoptosis. Naturally occurring antibodies against Bim (NAbs-Bim) exist in human blood, with their levels and functions unknown in AD. Methods This study investigated the clinical relevance of plasma NAbs-Bim to AD in 55 AD patients, 28 patients with non-AD dementia, and 70 cognitively normal subjects. Furthermore, the pathophysiological functions of NAbs-Bim were explored in APP/PS1 mice and SY5Y cell lines overexpressing human amyloid precursor protein (APP). Results We found that plasma levels of NAbs-Bim were lower in AD patients in comparison with patients with non-AD dementia and cognitively normal controls. Plasma levels of NAbs-Bim were negatively associated with brain amyloid burdens and positively associated with cognitive functions. NAbs-Bim purified from intravenous immunoglobulin rescued behavioral deficits of APP/PS1 mice. NAbs-Bim ameliorated Aβ deposition, Tau hyperphosphorylation, microgliosis and neuronal apoptosis in APP/PS1 mice. In vitro investigations demonstrated that NAbs-Bim exerted neuroprotective effects against AD through neutralizing Bim-directed neuronal apoptosis and amyloidogenic processing of amyloid precursor protein. Conclusions The decrease of NAbs-Bim might contribute to the pathogenesis of AD and immunotherapies targeting Bim may hold promise for the treatment of AD.

Association of naturally occurring antibodies to β-amyloid with cognitive decline and cerebral amyloidosis in Alzheimer’s disease

The pathological relevance of naturally occurring antibodies to β-amyloid (NAbs-Aβ) in Alzheimer’s disease (AD) remains unclear. We aimed to investigate their levels and associations with Aβ burden and cognitive decline in AD in a cross-sectional cohort from China and a longitudinal cohort from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. NAbs-Aβ levels in plasma and cerebrospinal fluid (CSF) were tested according to their epitopes. Levels of NAbs targeting the amino terminus of Aβ increased, and those targeting the mid-domain of Aβ decreased in both CSF and plasma in AD patients. Higher plasma levels of NAbs targeting the amino terminus of Aβ and lower plasma levels of NAbs targeting the mid-domain of Aβ were associated with higher brain amyloidosis at baseline and faster cognitive decline during follow-up. Our findings suggest a dynamic response of the adaptive immune system in the progression of AD and are relevant to current passive immunotherapeutic strategies.

Profiling of Naturally Occurring Antibodies to the Thomsen-Friedenreich Antigen in Health and Cancer: The Diversity and Clinical Potential

The Thomsen-Friedenreich (TF) antigen is expressed in a majority of human tumors due to aberrant glycosylation in cancer cells. There is strong evidence that humoral immune response to TF represents an effective mechanism for the elimination of cancer cells that express TF-positive glycoconjugates. The presence of naturally occurring antibodies to tumor-associated TF and cancer-specific changes in their levels, isotype distribution and interrelation, avidity, and glycosylation profile make these Abs a convenient and ubiquitous marker for cancer diagnostics and prognostics. In this review, we attempt to summarize the latest data on the potential of TF-specific Abs for cancer diagnostics and prognostics.

Survival of Recombinant Monoclonal Antibodies (IgG, IgA and sIgA) Versus Naturally-Occurring Antibodies (IgG and sIgA/IgA) in an Ex Vivo Infant Digestion Model

To prevent infectious diarrhea in infants, orally-supplemented enteric pathogen-specific recombinant antibodies would need to resist degradation in the gastrointestinal tract. Palivizumab, a recombinant antibody specific to respiratory syncytial virus (RSV), was used as a model to assess the digestion of neutralizing antibodies in infant digestion. The aim was to determine the remaining binding activity of RSV F protein-specific monoclonal and naturally-occurring immunoglobulins (Ig) in different isoforms (IgG, IgA, and sIgA) across an ex vivo model of infant digestion. RSV F protein-specific monoclonal immunoglobulins (IgG, IgA, and sIgA) and milk-derived naturally-occurring Ig (IgG and sIgA/IgA) were exposed to an ex vivo model of digestion using digestive samples from infants (gastric and intestinal samples). The survival of each antibody was tested via an RSV F protein-specific ELISA. Ex vivo gastric and intestinal digestion degraded palivizumab IgG, IgA, and sIgA (p < 0.05). However, the naturally-occurring RSV F protein-specific IgG and sIgA/IgA found in human milk were stable across gastric and intestinal ex vivo digestion. The structural differences between recombinant and naturally-occurring antibodies need to be closely examined to guide future design of recombinant antibodies with increased stability for use in the gastrointestinal tract.

Naturally occurring antibodies in cats against dog erythrocyte antigens and vice versa

Objectives The aim of this study was to investigate the presence of naturally occurring antibodies against canine erythrocyte antigens in cats and vice versa. The influence of canine and feline blood type on cross-match results was also studied. Methods Blood samples from 34 cats and 42 dogs were used to perform test tube major and minor cross-match tests and blood typing. Blood from each cat was cross-matched with blood from 2–6 dogs, for a total of 111 cross-match tests. Haemolysis, macro- and microagglutination were considered markers of a positive cross-match. Results Eighty-three overall major cross-match tests were positive at 37°C, 86 at room temperature and 90 at 4°C. The minor cross-match tests were positive in all but two cross-matches performed at 37°C, all tests performed at room temperature and all but one test performed at 4°C. No cats tested totally negative at both major and minor cross-matches performed with samples from any single dog. Prevalence of warm natural antibodies against canine erythrocyte antigens was lower in type B cats than in type A cats, regardless of the blood type of donor dogs. Conclusions and relevance This study reveals a high prevalence of naturally occurring antibodies in cats against dog erythrocyte antigens and vice versa, and suggests that transfusion of cats with canine blood is not recommended as a routine procedure owing to the potential high risk of either acute severe or milder transfusion reactions.