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Cryptic natural autoantibodies and co-potentiators

Cheng HM, Chamley L

Autoimmun Rev, 2008 Jun;7(6):431-4.
PMID: 18558357 DOI: 10.1016/j.autrev.2008.03.011

Natural autoantibodies are normal components of the humoral arm of the immune system found in clinically healthy individuals. There are two subpopulations of natural antibodies, including an overt group of antibodies that are readily detected in unfractionated normal human sera. The other natural antibody subgroup is revealed by physico or biochemical treatment of normal human sera in vitro. Unmasking of this latter cryptic natural autoantibodies (cNA) may occur in vivo by local factors in the tissue environment of disease states. The masking cryptic factors may be immunoglobulin (Ig) or non-Ig in nature. These factors may either be co-inhibitors or co-enhancers of cNA. In the heat-potentiated binding of natural anti-phospholipid antibodies, apolipoprotein H (beta 2-glycoprotein I) appears to act as a co-enhancer. The immuno-relationship between the in vitro and in vivo cNA phenomenon remains to be elucidated.
The clinical relevance of sexual dysfunction in systemic sclerosis

Bruni C, Raja J, Denton CP, Matucci-Cerinic M

Autoimmun Rev, 2015 Dec;14(12):1111-5.
PMID: 26235995 DOI: 10.1016/j.autrev.2015.07.016

Systemic sclerosis is a chronic multi-organ autoimmune disease, leading to important clinical and psychological implications. Among organ complications, sexual dysfunction is a major issue for both male and female gender, with high prevalence and great impact on quality of life, although frequently not addressed by both clinicians and patients. While erectile dysfunction is the most common cause of sexual problems in males, genital tract and general physical changes are major contributors to sexual impairment in females. This review presents current state of the art on this topic, discussing published data on presentation, evaluation and therapeutic options.
Vitamin D status in patients with systemic lupus erythematosus (SLE): A systematic review and meta-analysis

Islam MA, Khandker SS, Alam SS, Kotyla P, Hassan R

Autoimmun Rev, 2019 Sep 11.
PMID: 31520805 DOI: 10.1016/j.autrev.2019.102392

BACKGROUND: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease where chronic inflammation and tissue or organ damage is observed. Due to various suspected causes, inadequate levels of vitamin D (a steroid hormone with immunomodulatory effects) has been reported in patients with SLE, however, contradictory.
AIMS: The aim of this systematic review and meta-analysis was to evaluate the serum levels of vitamin D in patients with SLE in compared to healthy controls.
METHODS: PubMed, SCOPUS, ScienceDirect and Google Scholar electronic databases were searched systematically without restricting the languages and year (up to March 2, 2019) and studies were selected based on the inclusion criteria. Mean difference (MD) along with 95% confidence intervals (CI) were used and the analyses were carried out by using a random-effects model. Different subgroup and sensitivity analyses were conducted. Study quality was assessed by the modified Newcastle-Ottawa Scale (NOS) and publication bias was evaluated by a contour-enhanced funnel plot, Begg's and Egger's tests.
RESULTS: We included 34 case-control studies (2265 SLE patients and 1846 healthy controls) based on the inclusion criteria. Serum levels of vitamin D was detected significantly lower in the SLE patients than that in the healthy controls (MD: -10.44, 95% CI: -13.85 to -7.03; p 
Fulltext Positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging of macrophages in large vessel vasculitis: Current status and future prospects

Jiemy WF, Heeringa P, Kamps JAAM, van der Laken CJ, Slart RHJA, Brouwer E

Autoimmun Rev, 2018 Jul;17(7):715-726.
PMID: 29729443 DOI: 10.1016/j.autrev.2018.02.006

Macrophages are key players in the pathogenesis of large-vessel vasculitis (LVV) and may serve as a target for diagnostic imaging of LVV. The radiotracer, 18F-FDG has proven to be useful in the diagnosis of giant cell arteritis (GCA), a form of LVV. Although uptake of 18F-FDG is high in activated macrophages, it is not a specific radiotracer as its uptake is high in any proliferating cell and other activated immune cells resulting in high non-specific background radioactivity especially in aging and atherosclerotic vessels which dramatically lowers the diagnostic accuracy. Evidence also exists that the sensitivity of 18F-FDG PET drops in patients upon glucocorticoid treatment. Therefore, there is a clinical need for more specific radiotracers in imaging GCA to improve diagnostic accuracy. Numerous clinically established and newly developed macrophage targeted radiotracers for oncological and inflammatory diseases can potentially be utilized for LVV imaging. These tracers are more target specific and therefore may provide lower background radioactivity, higher diagnostic accuracy and the ability to assess treatment effectiveness. However, current knowledge regarding macrophage subsets in LVV lesions is limited. Further understanding regarding macrophage subsets in vasculitis lesion is needed for better selection of tracers and new targets for tracer development. This review summarizes the development of macrophage targeted tracers in the last decade and the potential application of macrophage targeted tracers currently used in other inflammatory diseases in imaging LVV.
Antiphospholipid antibodies in epilepsy: A systematic review and meta-analysis

Islam MA, Alam F, Cavestro C, Calcii C, Sasongko TH, Levy RA, et al.

Autoimmun Rev, 2018 Aug;17(8):755-767.
PMID: 29885542 DOI: 10.1016/j.autrev.2018.01.025

BACKGROUND: Autoimmunity is believed to play an important causative role in the pathogenesis of epilepsy. There are evidences for the presence of autoantibodies in patients with epilepsy. To date, many studies have assessed the presence of antiphospholipid antibodies (aPLs) in epilepsy patients, though the relationship has been inconclusive.

AIMS: The aim of this systematic review and meta-analysis was to evaluate the presence of aPLs in epileptic patients as compared to healthy controls.

METHODS: Five electronic databases (PubMed, Web of Science, Embase, Scopus and Google Scholar) were searched systematically. Study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using random-effects model. Quality assessment was carried out by using the modified 9-star Newcastle-Ottawa Scale (NOS). L'Abbé plots were generated to visually inspect heterogeneity while publication bias was evaluated via visualization of contour- enhanced funnel plots, and Begg's and Egger's tests.

RESULTS: Based on the inclusion criteria, 14 studies were selected involving 1248 epilepsy patients and 800 healthy controls. The majority of epilepsy was categorised as generalised or partial and none had comorbidity with autoimmune diseases. Significant presence of both anticardiolipin (aCL) antibodies (OR: 5.16, 95% CI: 3.21-8.28, p 
Genetic risk factors in thrombotic primary antiphospholipid syndrome: A systematic review with bioinformatic analyses

Islam MA, Khandker SS, Alam F, Kamal MA, Gan SH

Autoimmun Rev, 2018 Mar;17(3):226-243.
PMID: 29355608 DOI: 10.1016/j.autrev.2017.10.014

BACKGROUND: Antiphospholipid Syndrome (APS) is an autoimmune multifactorial disorder. Genetics is believed to play a contributory role in the pathogenesis of APS, especially in thrombosis development and pregnancy morbidity. In the last 20 years, extensive research on genetic contribution on APS indicates that APS is a polygenic disorder, where a number of genes are involved in the development of its clinical manifestations.

AIMS: The aim of this systematic review is to evaluate the genetic risk factors in thrombotic primary APS. Additionally, to assess the common molecular functions, biological processes, pathways, interrelations with the gene encoded proteins and RNA-Seq-derived expression patterns over different organs of the associated genes via bioinformatic analyses.

METHODS: Without restricting the year, a systematic search of English articles was conducted (up to 4th September 2017) using Web of Science, PubMed, Scopus, ScienceDirect and Google Scholar databases. Eligible studies were selected based on the inclusion criteria. Two researchers independently extracted the data from the included studies. Quality assessment of the included studies was carried out using a modified New-Castle Ottawa scale (NOS).

RESULTS: From an initial search result of 2673 articles, 22 studies were included (1268 primary APS patients and 1649 healthy controls). Twenty-two genes were identified in which 16 were significantly associated with thrombosis in primary APS whereas six genes showed no significant association with thrombosis. Based on the NOS, 14 studies were of high quality while 6 were low quality studies. From the bioinformatic analyses, thrombin-activated receptor activity (q = 6.77 × 10-7), blood coagulation (q = 2.63 × 10-15), formation of fibrin clot (q = 9.76 × 10-10) were the top hit for molecular function, biological process and pathway categories, respectively. With the highest confidence interaction score of 0.900, all of the thrombosis-associated gene encoded proteins of APS were found to be interconnected except for two. Based on the pathway analysis, cumulatively all the genes affect haemostasis [false discovery rate (FDR) = 1.01 × 10-8] and the immune system [FDR = 9.93 × 10-2]. Gene expression analysis from RNA-Seq data revealed that almost all the genes were expressed in 32 different tissues in the human body.

CONCLUSION: According to our systematic review, 16 genes contribute significantly in patients with thrombotic primary APS when compared with controls. Bioinformatic analyses of these genes revealed their molecular interconnectivity in protein levels largely by affecting blood coagulation and immune system. These genes are expressed in 32 different organs and may pose higher risk of developing thrombosis anywhere in the body of primary APS patients.
Comorbid association of antiphospholipid antibodies and migraine: A systematic review and meta-analysis

Islam MA, Alam F, Wong KK

Autoimmun Rev, 2017 May;16(5):512-522.
PMID: 28279839 DOI: 10.1016/j.autrev.2017.03.005

BACKGROUND: Antiphospholipid antibodies (aPLs) namely anticardiolipin (aCL) antibody, anti-β2-glycoprotein I (β2GPI) antibody and lupus anticoagulant (LA) are autoantibodies produced against anionic phospholipids and proteins on plasma membranes. Migraine is a primary headache disorder which has growing evidences of autoimmune-mediated pathogenesis and previous studies suggested the presence of aPLs in migraine patients.

AIMS: The aim of this study was to evaluate the comorbid association between aPLs (aCL, anti-β2GPI and LA) and migraine compared to healthy controls.

METHODS: Studies were searched through PubMed, ISI Web of Science and Google Scholar databases without restricting the languages and year (up to October 2016) and were selected based on the inclusion criteria. Two authors independently extracted data from the included studies. All analyses were conducted by using random effects model to calculate the odds ratio (OR) and 95% confidence interval (CI). Quality assessment was carried out by using the modified Newcastle-Ottawa Scale (NOS). Publication bias was evaluated via visualization of funnel plots, Begg's and Egger's tests.

RESULTS: The database searches produced 1995 articles, 13 of which were selected (912 migraineurs and 822 healthy controls). 8.59%, 15.21% and 4.11% of the migraineurs exhibited aCL, anti-β2GPI and LA which was 4.83, 1.63 and 3.03 times higher, respectively, than healthy controls. A significant presence of aCL (OR: 3.55, 95% CI: 1.59-7.95; p=0.002) or anti-β2GPI antibodies (OR: 2.02, 95% CI: 1.20-3.42; p=0.008) was observed in migraine patients, however, LA was not significantly associated (OR: 2.02, 95% CI: 0.50-8.37; p=0.320). Majority of the studies (n=10 of 13) demonstrated NOS score of 7 or above and no significant publication bias was observed.

CONCLUSION: Migraine might be an autoimmune-associated neurologic disorder. The presence of aCL or anti-β2GPI antibodies was significant in migraine patients compared to healthy controls, suggesting an involvement of these autoantibodies in migraine attack.
Potential immunological and genetic markers associated with lupus nephritis: From pathogenicity to therapeutic drug target

Sharafaldin ENK, Huri HZ, Sim MS, Lim SK

Autoimmun Rev, 2023 Dec;22(12):103406.
PMID: 37574180 DOI: 10.1016/j.autrev.2023.103406