Immunoglobulin Type Research Articles

Clinical laboratory diagnostics of antibodies to SARS-CoV-2: from a QR code to the reality

Background: The immune response to SARS-CoV-2 includes the production of specific immunoglobulins to protein antigens of SARS-CoV-2. Depending on the type and level of immunoglobulins, it is possible to assess the stage of the disease and evaluate the effectiveness of vaccination. The main approach to the determination of immunoglobulins to SARS-CoV-2 in human biological fluids is enzyme-linked sorbent immunoassay. Its data, in particular, are used to issue an electronic COVID-19 certificate with a QR code. However, the qualitative and quantitative composition of immunoglobulins for a QR code is not officially regulated. Aim: measuring the immunoglobulins level in the human blood serum with different types of immunity to the new coronavirus infection (COVID-19) to select the most informative indicators of protective immunity. Methods: The study included 76 blood serum samples from male and female volunteers (age, 18 to 50 y.o.) in compliance with the ethical standards. The detection of IgA, IgM, IgG (total to different regions of SARS-CoV-2, S-protein IgG and RBD-fragment IgG), IgG avidity, and the level of the SARS-CoV-2 N-antigen was performed by enzyme-linked immunosorbent assay (ELISA) using commercially available reagent kits. Results: The indicators of the level of antibodies (both "protective" IgG and IgA of the initial phase of infection) are most pronounced in persons who have been vaccinated and have had COVID-19, and least pronounced in unvaccinated people. For recovered unvaccinated individuals, the level of total protective antibodies and IgG to the S-protein, including the RBD fragment, is the lowest; the avidity of IgG is lower than that in the other groups, too. The IgG avidity in vaccinated patients is higher than that in recovered ones. It should be noted that there were no differences in the level of both total IgG to SARS-CoV-2, to the S-protein and to the RBD-fragment of the S-protein for recovered and vaccinated individuals. Conclusion: The analysis of COVID-19 immunoglobulins indicates a different profile of the humoral immune response following vaccination and previous infection with COVID-19. To quickly assess the immune response to previous and current COVID-19 infection, as well as to detect the post-vaccination immunity, it is advisable to use the total level of IgG to SARS-CoV-2. For deeper assessment of protective immunity and production of protective antibodies, it is better to evaluate the quantitative content of IgG to the S protein and its RBD fragment. The equal level of IgA in the experimental groups indicates an ongoing interaction with SARS CoV-2 in the population. Thus, the electronic COVID-19 certificate is of little use when it is formed by only one of the indicators without taking into account the rest.

The epidemiology of Waldenström macroglobulinemia

Waldenström macroglobulinemia (WM) is a rare subtype of non-Hodgkin lymphoma characterized by the presence of lymphoplasmacytic lymphoma (LPL) in the bone marrow accompanied by a monoclonal immunoglobulin type M (IgM) in the serum. WM was first described only 80 years ago and became reportable in the US as a malignancy in 1988. Very little systematic research was conducted prior to 2000 to characterize incidence, clinical characteristics, risk factors or diagnostic and prognostic criteria, and there were essentially no WM-specific clinical interventional trials. Since the inaugural meeting of the International Workshop in Waldenström's Macroglobulinemia (IWWM) in 2000, WM has become the focus of a steadily increasing and productive body of research, engaging a growing number of investigators throughout the world. This introductory overview provides summary of the current understanding of the epidemiology of WM/LPL as a backdrop for a series of consensus panel recommendations arising from research presented at the 11th IWWM.

Immunoglobulins response of COVID-19 patients, COVID-19 vaccine recipients, and random individuals.

The development of specific immunoglobulins to COVID-19 after natural infection or vaccination has been proposed. The efficacy and dynamics of this response are not clear yet. This study aims to analyze the immunoglobulins response among COVID-19 patients, COVID-19 vaccine recipients and random individuals. A total of 665 participants including 233 COVID-19 patients, 288 COVID-19 vaccine recipients, and 144 random individuals were investigated for anti-COVID-19 immunoglobulins (IgA, IgG, IgM). Among COVID-19 patients, 22.7% had detectable IgA antibodies with a mean of 27.3±57.1 ng/ml, 29.6% had IgM antibodies with a mean of 188.4±666.0 BAU/ml, while 59.2% had IgG antibodies with a mean of 101.7±139.7 BAU/ml. Pfizer-BioNTech vaccine recipients had positive IgG in 99.3% with a mean of 515.5±1143.5 BAU/ml while 85.7% of Sinopharm vaccine recipients had positive IgG with a mean of 170.0±230.0 BAU/ml. Regarding random individuals, 54.9% had positive IgG with a mean of 164.3±214 BAU/ml. The peak IgM response in COVID-19 patients was detected early at 15-22 days, followed by IgG peak at 16-30 days, and IgA peak at 0-60 days. IgM antibodies disappeared at 61-90 days, while IgG and IgA antibodies decreased slowly after the peak and remained detectable up to 300 days. The frequency of IgG positivity among patients was significantly affected by increased age, admission department (inpatient or outpatient), symptoms, need for oxygen therapy, and increased duration between positive COVID-19 RT PCR test and serum sampling (p˂0.05). Positive correlations were noted between different types of immunoglobulins (IgG, IgM, and IgA) among patients. Natural infection and COIVD-19 vaccines provide IgG-mediated immunity. The class, positivity, mean, efficacy, and duration of immunoglobulins response are affected by the mechanism of immunity and host related variables. Random community individuals had detectable COVID-19 IgG at ~55%, far from reaching herd immunity levels.

Comparative Analysis of the Humoral Immune Response to the EBV Proteome across EBV-Related Malignancies.

Epstein-Barr virus (EBV) is linked to multiple cancers, including classical Hodgkin lymphoma (cHL), endemic Burkitt lymphoma (eBL), nasopharyngeal carcinoma (NPC), and extranodal natural killer/T-cell lymphoma (NKTCL). Anti-EBV IgG and IgA antibody responses targeting 202 sequences from 86 EBV proteins were measured using the same EBV whole proteome array across four case-control studies investigating EBV-positive cHL, eBL, NPC, and NKTCL (407 cases/620 controls). We grouped EBV-targeted antibodies into pathways by immunoglobulin type (IgA and IgG) and life-cycle stage (latent, immediate early lytic, early lytic, late lytic, and glycoprotein) and evaluated their association with each cancer type. In an additional analysis, we focused on the subset of 46 individual antibodies representing the top candidates for each cancer and compared their associations across the four cancer types using multivariable linear regression models. IgA antibody responses targeting all EBV life-cycle stages were associated with NPC but limited to anti-early lytic stage for cHL. NPC and eBL were associated with IgG antibodies across the viral life cycle; cHL with antibodies in the early lytic, late lytic and glycoprotein stages; and NKTCL with antibodies in the latent, immediate early lytic and early lytic phases. EBNA3A, BBLF1, BDLF4, and BLRF2 IgG antibodies were associated with all cancer types. Our observed similarities and differences across four EBV-associated cancers may inform EBV-related oncogenesis. Understanding the comparative humoral immune response across EBV-related cancers may aid in identifying shared etiologic roles of EBV proteins and inform unique pathogenic processes for each cancer.

Clinical characteristics and progression risk factors for patients with monoclonal gammopathy of undetermined significance

Objective: To analyze the clinical presentation and progression risk factors of patients with monoclonal gammopathy of undetermined significance (MGUS) in China. Methods: We retrospectively assessed the clinical features and disease progression of 1 037 patients with monoclonal gammopathy of undetermined significance between January 2004 and January 2022 at Peking Union Medical College Hospital. Results: A total of 1 037 patients were recruited in the study, including 636 males (63.6%) , with a median age of 58 (18-94) years. The median concentration of serum monoclonal protein was 2.7 (0-29.4) g/L. The monoclonal immunoglobulin type was IgG in 380 patients (59.7%) , IgA in 143 patients (22.5%) , IgM in 103 patients (16.2%) , IgD in 4 patients (0.6%) , and light chain in 6 patients (0.9%) . 171 patients (31.9%) had an abnormal serum-free light chain ratio (sFLCr) . According to the Mayo Clinic model for risk of progression, the proportion of patients in the low-risk, medium-low-risk, medium-high risk, and high-risk groups were 254 (59.5%) , 126 (29.5%) , 43 (10.1%) , and 4 (0.9%) , respectively. With a median follow-up of 47 (1-204) months, 34 of 795 patients (4.3%) had disease progression, and 22 (2.8%) died. The overall progression rate was 1.06 (0.99-1.13) /100 person-years. Patients with non-IgM MGUS have a markedly higher disease progression rate per 100 person-years than IgM-MGUS (2.87/100 person-years vs 0.99/100 person-years, P=0.002) . The disease progression rate per 100 person-years in non-IgM-MGUS patients of Mayo classification low-risk, medium-low risk and medium-high risk groups were 0.32 (0.25-0.39) /100 person-years, 1.82 (1.55-2.09) /100 person-years, and2.71 (1.93-3.49) /100 person-years, which had statistically difference (P=0.005) . Conclusion: In comparison to non-IgM-MGUS, IgM-MGUS has a greater risk of disease progression. The Mayo Clinic progression risk model applies to non-IgM-MGUS patients in China.

C1-inhibitor/C1-inhibitor antibody complexes in acquired angioedema due to C1-inhibitor deficiency

BackgroundAutoantibodies against C1-inhibitor (C1-INH-Ab) have a diagnostic value in acquired angioedema due to C1-inhibitor deficiency (C1-INH-AAE), even though antibodies can circulate in complexes, which can be undetectable by proven methods. Our aim was to measure C1-INH/C1-INH-Ab complexes (CAC) and investigate their connection to C1-INH-Ab and the changes in their titer over time.Results19 patients were diagnosed with C1-INH-AAE in the Hungarian Angioedema Center of Reference and Excellence; 79% of them had an underlying disease. Samples were examined with a newly developed in-house complex ELISA method. Patients with high C1-INH-Ab titer had a CAC titer which did not exceed the normal level and the ones with high CAC titer had a C1-INH-Ab titer which did not exceed the normal level. In case of those patients who had C1-INH-Ab and CAC of the same type of immunoglobulin, the increasing titer of C1-INH-Ab went together with the decreasing level of CAC and vice versa. CAC titer was already increased before the diagnosis of the underlying disease.ConclusionsFree circulating and complex antibodies are in a dynamically changing equilibrium. CAC measurements can help to predict the development of an underlying disease. The efficiency of the treatment for underlying disease can be monitored by the decreasing CAC titers.Our results show that the CAC can be of important additional information besides the complement panel examination in case of C1-INH-AAE. Measurement of CAC is recommended to be done parallelly with C1-INH-Ab, so as to detect both free and bound antibodies.

Serum biomarkers for nutritional status as predictors in COVID-19 patients before and after vaccination.

The aim of this study was to characterize serum protein biomarkers for nutritional status that may be used as predictors for disease symptomatology in COVID-19 patients before and after vaccination. In pre-vaccine cohorts, proteomics analysis revealed significant differences between groups, with serum proteins alpha-1-acid glycoproteins (AGPs) 1 and 2, C-reactive protein (CRP) and retinol binding protein (RBP) increasing with COVID-19 severity, in contrast with serum albumin, transthyretin (TTR) and serotransferrin (TF) reduction as the symptomatology increased. Immunoassay reproduced and validated proteomics results of serum proteins albumin and RBP. In post-vaccine cohorts, the results showed the same pattern as in pre-vaccine cohorts for serum proteins AGPs, CRP, albumin and TTR. However, TF levels were similar between groups and RBP presented a slight reduction as COVID-19 symptomatology increased. In these cohorts, immunoassay validated proteomics results of serum proteins albumin, TTR and TF. Additionally, immune response to α-Gal in pre-vaccine cohorts varied in predominant immunoglobulin type profile, while post-vaccine groups presented mainly anti-α-Gal protective IgG antibodies. The study identified serum nutritional biomarkers that could potentially predict an accurate prognostic of COVID-19 disease to provide an appropriate nutritional care and guidance in non-vaccinated and vaccinated individuals against SARS-CoV-2. These results highlight the importance of designing personalized nutrition protocols to improve diet along with the application of prebiotics or probiotics for the control of COVID-19 and other infectious diseases.

Analisis Titer dan Subtipe Antibodi pada Inkompatibilitas ABO yang Menyebabkan Hemolytic Disease of Fetus and Newborn

Background: Hemolytic disease of the fetus and newborn (HDFN) is a type of anemia in the fetus or newborn. Clinical features of HDFN such as hepatosplenomegaly, liver failure, ascites, at birth die from heart failure to brain damage. One of the most common causes is incompatibility of blood groups such as ABO. Differences in clinical manifestations that occur in HDFN are caused by differences in antibody titers and IgG subtypes.Objective: The aim of this study was to determine the anti-A and anti-B antibody titers and the types of immunoglobulins that affect HDFN due to ABO incompatibility.Methods: The sample used in this study was blood and umbilical cord blood from 30 pairs of mother-babies who had different blood groups. Titration examination by tube method and IgG subtype by ELISA method were performed on maternal samples.Results: The correlation of total bilirubin levels with maternal Anti-A and Anti-B titers are p= 0.023 and p= 0.001, in addition there are significant increase in OD of Anti-A IgG1 and Anti-B IgG1 againts elevated infant bilirubin levels.Conclusion: IgG titers >8 causing hyperbilirubinemia, but no jaundice and IgG titers >16 causing hyperbilirubinemia to jaundice. The IgG subtype that plays a more role in causing clinical problems is IgG1.

A comprehensive review on preparation of pure immunoglobulins Authors

Immunoglobulins are also known as antibodies. Plasma cells are responsible for the production of immunoglobulins. Beta cells are activated against a pathogenic attack and facilitated the formation of different types of immunoglobulins naturally. These immunoglobulins are also artificially synthesized by non-specific laboratorial techniques include fractionation precipitation, electrophoretic methods, gel filtration chromatography, ion exchange chromatography, hydrophobic chromatography and by the specific immuno- adsorbent methods. Third generation immunoglobulins are effectively used for therapeutic purpose against viral infections intravenously. Second generation immunoglobulins synthesis involved removal of anti-complement contaminants and IgG aggregates, through enzymatic degradation and chemical modification. The harmful effects of intravenous immunoglobulins can be reduced by using ultraviolet light, P-propiolactone, and pepsin at pH 4. Intravenous immunoglobulin drugs lead to anti-inflammatory and immunomodulatory effects in various infections. The mechanism of action of intravenous immunoglobulins is dependent on the binding between the Fc portion of injected IgG and target cell receptors. Radiolabeling is performed by two methods as in vivo, in which radiolabeled antibodies are incorporated into the body to bind with the antibodies and in vitro method, radioactive material is bound with already formed antibodies. This chapter highlighted the artificial methods adopted for production of radiolabeled immunoglobulins holding significant therapeutic and diagnostic applications.

Immunoproteomics of cow's milk allergy in Mexican pediatric patients

Immunological mechanisms of non-IgE-mediated cow's milk protein allergy (CMPA) are not well understood. Such a circumstance requires attention with the aim of discovering new biomarkers that could lead to better diagnostic assays for early treatment. Here, we sought both to investigate the mechanism that underlies non-IgE-mediated CMPA and to identify cow's milk immunoreactive proteins in a Mexican pediatric patient group (n = 34). Hence, we determined the IgE and IgG1–4 subclass antibody levels against cow's milk proteins (CMP) by ELISA. Then, we performed 2D-Immunoblots using as first antibody immunoglobulins in the patients'serum that bound specifically against CMP together with CMP enrichment by ion-exchange chromatography. Immunoreactive proteins were identified by mass spectrometry-based proteomics. The serological test confirmed absence of specific IgE in the CMPA patients but showed significant increase in antigen-specific IgG1. Additionally, we identified 11 proteins that specifically bound to IgG1. We conclude that the detection of specific IgG1 together with an immunoproteomics approach is highly relevant to the understanding of CMPA's physiopathology and as a possible aid in making a prognosis since current evidence indicates IgG1 occurrence as an early signal of potential risk toward development of IgE-mediated food allergy. SignificanceAllergies are one of the most studied topics in the field of public health and novel protein allergens are found each year. Discovery of new principal and regional allergens has remarkable repercussions in precise molecular diagnostics, prognostics, and more specific immunotherapies. In this context, specific IgE is widely known to mediate physiopathology; however, allergies whose mechanism does not involve this immunoglobulin are poorly understood although their incidence has increased. Therefore, accurate diagnosis and adequate treatment are delayed with significant consequences on the health of pediatric patients. The study of type and subtypes of immunoglobulins associated with the immunoreactivity of cow's milk proteins together with an immunoproteomics approach allows better comprehension of physiopathology, brings the opportunity to discover new potential cow's milk protein allergens and may help in prognosis prediction (IgG1 occurrence as an early signal of possible risk toward development of IgE-mediated food allergy).

Characteristics and Outcomes of Multiple Myeloma in Hispanic Versus Non-Hispanic Patients in Central California

Background: Multiple Myeloma (MM) accounts for roughly 10% of all hematologic cancers in the U.S., with 37% of MM patients being non-white minorities. Advanced stage at diagnosis and specific cytogenetic abnormalities are associated with high-risk disease and poor prognosis. Studies evaluating these risk factors, however, consisted of mostly Caucasian patients with an underrepresentation of ethnic minorities. In the phase III DETERMINATION trial, ~18% of the study population was Black compared to only ~6% Hispanic, with the rest being Caucasian. Although this study showed significant overall progression free survival (PFS) benefit in transplant patients, this was not seen in the Black patient subgroup. To further investigate outcomes of other ethnic MM patients in the Central Valley of CA, we analyzed characteristics and outcomes of MM patients who were seen at Community Medical Centers in Fresno CA (49.6% Hispanic population). Methods: Patients diagnosed with MM at Community Medical Centers from January 2011 to December 2020 were included. High risk disease was defined by the Mayo Clinic mSMART 3.0 classification. Demographic and disease-relevant information including age at diagnosis, gender, ethnicity (Hispanic vs non-Hispanic), insurance, median income by zip code, laboratory data at diagnosis (hemoglobin, creatinine, corrected Ca, LDH, beta 2 microglobulin), immunoglobulin type, light chain type, cytogenetic abnormalities, stage (R-ISS), 1st line treatment (doublet vs triplet), transplant status, and treatment response (IMWG response criteria) were collected. Comparisons between Hispanics and non-Hispanics were made by Fisher's exact test and nonparametric equality-of-medians test where appropriate. Outcomes were compared via log-rank testing and Kaplan-Meier estimates for 2 year PFS and overall survival (OS). Univariate cox proportional hazard model for survival was used to examine the association of demographic and MM variables with mortality risk after first line therapy. Results: 117 MM patients were included with 42 high risk patients identified (11 Hispanic, 31 non-Hispanic). Median age at diagnosis of Hispanics vs non-Hispanics was 61.7 vs 66.5 years (p=0.046). Hispanic vs non-Hispanic median income was $49734.50 vs $62588.90 (p=0.003). Insurance status differed significantly with more Hispanics having Medi-Cal and non-Hispanics having private/Medicare (p=0.001). 13 non-Hispanics had 17p del vs 0 Hispanics (p=0.001). Hispanics and non-Hispanics did not have significantly different responses to first line therapy per IMWG criteria (p=0.535). Hispanic and non-Hispanic patients experienced similar 2 year PFS and OS (PFS: 63% vs. 60%, p=0.744; OS: 94% vs 85%, p=0.145). 14 Hispanics and 20 non-Hispanics underwent autologous stem cell transplant. No significant difference in 2 year PFS was seen in transplanted Hispanics vs transplanted non-Hispanics (p=0.228) and transplanted Hispanics vs non-transplant Hispanics (p=0.297). High risk transplanted Hispanics showed significantly worse 2 year PFS vs standard risk transplanted Hispanics (25% vs 80%, p=0.009). Transplanted Hispanics differed from non-transplant Hispanics by median age (55.5 vs 67, p=0.05) and income ($56510.00 vs $42418.00, p=0.01). Conclusions: Hispanic MM patients were younger at diagnosis, earned a lower median income, and had more Medicaid coverage compared to non-Hispanics. These differences did not translate to a difference in first line therapy, treatment response, or survival. Transplanted Hispanics were younger and had higher income than non-transplant Hispanics, suggesting that socioeconomic factors may play a role in transplant eligibility. Undergoing transplant, however, did not show a significant PFS benefit compared to Hispanics and non-Hispanics who did not undergo transplant. High risk Hispanics still had inferior PFS compared to standard risk Hispanics after transplant. Additional studies and longer follow-up are needed to confirm these findings. If validated, they could potentially influence treatment decisions for Hispanic MM patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Infectious Complications of B-Cell Maturation Antigen (BCMA)-Targeted Therapies for Relapsed/Refractory Multiple Myeloma

Background: Recently, therapeutics targeting B-cell Maturation Antigen (BCMA), including CAR T cells, bispecific antibodies (bsAbs) and antibody-drug conjugates (ADCs), have shown promise in improving outcomes in RRMM patients (pts). However, targeting BCMA can impair natural humoral immunity and increase infection risk. It remains unknown if BCMA-targeted therapies predispose pts to infection at higher frequency or with different characteristics than non-BCMA-targeted therapies in this RRMM population, or if the frequency and characteristics of infections differ amongst the various BCMA-targeted modalities. Methods: We conducted a single-center retrospective study of RRMM pts who started BCMA-targeted therapies (CAR T, bsAb, or ADC) or a selinexor-based treatment between Nov. 2015 and May 2021. We extracted data on patient demographics, MM characteristics, prior lines of therapy, neutrophil and lymphocyte counts, and response to therapy, as well as frequency, type, and severity of infections, quantitative immunoglobulins, and use of intravenous immunoglobulin (IVIG). Pts who had received serial BCMA-targeted therapies, or both a BCMA-targeted therapy and selinexor were excluded from analysis. Results: There were 134 pts included in the analysis: 112 who received a BCMA-targeted treatment (36 CAR T, 29 bsAb, and 47 ADC) and 22 who received selinexor-based treatment. Overall pt characteristics, including age, median lines of therapy, and %triple- and penta-refractory, were similar between the anti-BCMA therapy and selinexor groups, as well as amongst pts receiving the different anti-BCMA modalities. However median duration of therapy differed between groups, longest in the bsAb group and shortest for selinexor (Table 1). Of pts receiving BCMA-targeted treatment, 63 (56%) experienced at least 1 infectious complication (75% of CAR T, 48% of bsAb, and 47% of ADC pts), compared to 6 pts (27%) in the selinexor group. These 69 pts had a total of 146 infections (mean of 2.0, 2.9, 2.1, and 1.0 infections per infected pt in the CAR T, bsAb, ADC, and selinexor groups, respectively) (Table 2). Of the infections in the BCMA-treated pts, 70% were considered low-severity (no treatment or oral treatment alone) and 30% were high-severity (hospitalization, life-threatening, or fatal), with similar frequency of high-severity infections amongst pts getting CAR T, bsAb or ADC. Four of 6 infections (67%) in the selinexor group were high-severity. Most (66%) of the low-severity were upper respiratory tract infections, while most high-severity were lower respiratory tract infections (54%) or bacteremia (22%). Low-severity infections were most commonly viral, while high-severity infections were more likely bacterial. Fungal infections were rare (n=2, both in CAR-T patients). Median time to onset of high-severity infections was 59 days in the CAR T cohort compared to 278 days and 124 days in the bsAb and ADC groups, respectively, and 205 days in the selinexor group. Only 12 of the 146 infections (8%) occurred while pts were neutropenic. Median absolute lymphocyte counts (ALC) were low in all groups pre-treatment; amongst pts still on therapy at 3 months, median ALC had increased in all 3 BCMA-treated groups (Table 1). Regarding hypogammaglobulinemia we focused on pts with non-IgG myeloma to limit confounding effects of the monoclonal IgG protein. Amongst non-IgG pts receiving BCMA-targeted treatments (n=50), 70% had IgG<400 pre-treatment, which increased to 87% by 3 months. For non-IgG selinexor pts (n=9), these numbers were 67% and 71%, respectively. At least 1 dose of IVIG was given in 31% of BCMA-treated pts (22% of CAR T, 59% of bsAb, and 21% of ADC). Conclusions: RRMM pts treated with BCMA-targeted therapies are at high risk of developing an infectious complication, regardless of treatment modality, with many patients having multiple infections, and up to 30% developing high-severity infections. Infection frequency in this study appeared higher for anti-BCMA-treated pts than for selinexor-treated patients, though this finding is confounded by the small numbers and shorter duration of therapy in the selinexor group. Further analyses of the impact of response, ALC, immunoglobulin levels, and IVIG use on infection risk and severity are ongoing. These data demonstrate a need for optimizing strategies to prevent and treat infectious complications in RRMM pts receiving BCMA-targeted therapies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

One Case of POMES Syndrome with “Limb Pain” As the Main Presentation

Objective: To summarize the clinical manifestations, imaging features and gene mutation sites of a patient with pomes syndrome with “limb pain” as the main manifestation, so as to improve the understanding of this rare disease. Medical History: The patient was a 34 year old male with limb pain and fatigue for more than 20 days. Symptoms and Signs: The tongue is in the middle, the uvula is in the middle, the bilateral pharyngeal reflex disappears, the neck is soft, the muscle strength of both upper limbs is grade 5, the proximal muscle strength of both lower limbs is grade 4, and the distal muscle strength is grade 5. The muscle tension of the extremities is normal, the tendon reflex of the extremities disappears, and no obvious abnormalities are found in the examination of deep and shallow sensation and ataxia. The diagnostic method bone marrow puncture showed thrombocytosis. The pathological results showed that the hematopoietic cells of the three lines were proliferative, the oligoclonal bands in CSF were positive, and the oligoclonal bands in serum were positive. Serum immunofixation electrophoresis (March 30, 2018): IgG λ Abnormal monoclonal bands were found in the lane, and the type of monoclonal immunoglobulin was IgG- λ Type. Blood analysis suggested thrombocytosis (738 × 10°several L). There is no specific therapeutic drug, but hormone and hydroxyurea are effective. The clinical outcome was improved and the disease was gradually alleviated. The clinical conclusion is that poems syndrome is a rare clinical syndrome with various forms. Early intervention is effective for the prognosis of patients.

Variation in Milk Proteins Across Lactation in Pongo pygmaeus and Gorilla gorilla.

Milk is a critical nutrition source for all neonatal mammals. In addition to nutrition, milk contains a multitude of bioactive molecules that likely affect neonatal physiology, metabolism, and immune function. We suggest that changes in the milk proteome across lactation reflect the changing need of the neonate and juvenile offspring. We used mass spectrometry to characterize the milk proteomes from a Pongo pygmaeus (12 samples) and a Gorilla gorilla (6 samples) housed at the Smithsonian's National Zoo and Conservation Biology Institute and trained to give milk samples. We found a total of 454 proteins from P. pygmaeus and 428 proteins from G. gorilla. We specifically characterized changes across lactation in 13 proteins representing multiple compartments of milk, including the milk fat globule membrane and whey. Additionally, we characterized changes in various immunoglobulin types, finding similarities to previously published studies on primate milks. Despite broad similarities between the milk proteomes of these two apes, we demonstrated that proteomes from samples from 8 to 12 months clustered by species/individual and were distinct. Samples from more individuals are required to distinguish whether our result demonstrates species differences or individual differences. This study represents a baseline study that other zoo-based milk studies can build from. All RAW data, MetaMorpheus search results, and PAW_BLAST results are available on MassIVE at ftp://massive.ucsd.edu/MSV000089723/.

Intravenous and subcutaneous immunoglobulins-associated eczematous reactions occur with a broad range of immunoglobulin types: A French national multicenter study

Human immunoglobulins are used for treating diverse inflammatory and autoimmune disorders. Eczema is an adverse event reported but poorly described. To describe the clinical presentation, severity, outcome, and therapeutic management of immunoglobulin-associated eczema. This retrospective and descriptive study included a query of the French national pharmacovigilance database, together with a national call for cases among dermatologists. We included 322 patients. Eczema occurred preferentially in men (78.9%) and in patients treated for neurological pathologies (76%). The clinical presentation consisted mainly of dyshidrosis (32.7%) and dry palmoplantar eczema (32.6%); 5% of cases exhibited erythroderma. Sixty-two percent of the eczema flares occurred after the first immunoglobulin course. Eczema was observed with 13 intravenous or subcutaneous immunoglobulin types and recurred in 84% of patients who maintained the same treatment and in 68% who switched the immunoglobulin type. After immunoglobulin discontinuation, 30% of patients still had persistent eczema. Retrospective study, with possible missing data or memory bias. Immunoglobulin-associated eczema occurred with all immunoglobulin types, preferentially in patients with neurologic diseases who required prolonged immunoglobulin treatment. Recurrence was frequent, even after switching the immunoglobulin type, which can lead to a challenging therapeutic situation when immunoglobulin maintenance is required.

Expression of Twist 1 in bone marrow and extramedullary lesions of patients with myeloma and its prognostic significance

In patients with multiple myeloma (MM) extramedullary (EM) lesions could be a possible indicator of poor prognosis. Twist 1, an EMT related transcription factor, is known to play an important role in embryonic development and also in the process of tumor cell proliferation, apoptosis, metastasis etc. The Twist 1 protein expression hence has prognostic significance in MM. This study investigates expression of Twist-1 in MM patients with extramedullary lesions and its relationship with clinicopathological data and prognosis, so as to elucidate the clinical significance of Twist-1 expression. Patients with MM complicated with EM lesions were selected retrospectively, including 35 cases in the bone marrow group (MM complicated with extramedullary lesions) and 80 cases in the extramedullary group (MM combined with extramedullary lesions). The expression of Twist 1 protein was detected by immunohistochemistry. The relationship between Twist 1 protein expression and general clinicopathological data was analyzed by statistics. The relationship between Twist 1 protein expression and prognosis was analyzed by COX single factor and multivariate regression analysis. Immunohistochemical staining showed that the expression level of Twist-1 protein in the nucleus of myeloma cells in the extramedullary group was significantly higher than that of the bone marrow group. However, in the cytoplasm of myeloma cells, there was no significant difference in the expression level of Twist-1 protein between the extramedullary group and the bone marrow group. The expression level of Twist-1 protein in extramedullary tissue was not related to sex, age, D-S stage, ISS stage, immunoglobulin type, creatinine and hemoglobin. The expression level of β2-microglobulin in Twist-1 high expression group was significantly higher than that of Twist-1 low expression group. Follow-up findings discovered that overall survival (OS) of Twist 1 high expression group was significantly lower than that of Twist 1 low expression group. COX multivariate analysis showed that Twist 1 protein and International Staging System (ISS) stage were independent risk factors affecting OS for 3 years. The high expression rate of Twist 1 protein in extramedullary lesions of MM patients with extramedullary lesions is significantly higher than that in bone marrow tissues of patients with extramedullary lesions. The results suggest that high expression of Twist 1 protein is an independent risk factor affecting the prognosis of MM patients with extramedullary lesions.

S4 Autoimmune Pancreatitis Secondary to Immune Checkpoint Inhibitor Therapy (Type 3 AIP): Insights into a New Disease from Clinical Review and Serial Pancreatic Imaging

Introduction: Autoimmune pancreatitis (AIP), types 1 and 2, are well described. While type 1 AIP is a pancreatic manifestation of immunoglobulin G4-related disease (IgG4-RD) and type 2 AIP is a duct-centric pancreatic injury sometimes associated with inflammatory bowel disease. A third form of AIP (type 3) is caused by increased immune activity by immune checkpoint inhibitor therapy (ICI-℞) for advanced malignancies. We describe the clinico-radiological spectrum and short-term natural history of type 3 AIP. Methods: We performed a detailed clinical record review of the 248/11,165 (2.2%) adult patients receiving ICI-℞ who developed type 3 AIP (>3-fold serum lipase elevation + pain, absent other etiologies). A radiologist reviewed 379 abdominal computerized tomography scans (CT) and measured pancreas volume in a subset of CTs done before, during and after pancreatitis. Results: At onset, type 3 AIP was painful in 96 (38%) and asymptomatic in 154 (62%); none had jaundice or local/systemic complications. CT showed normal pancreas (43%), peri-pancreatic edema (27%), loss of feathery pattern (21%) or diffuse/focal pancreatic enlargement (10%). A minority achieved complete and persistent biochemical resolution, more often when ICI-℞ was held (32/89) vs no intervention (13/84, P = 0.003) or vs steroid treatment alone (2/23, P = 0.01). Early or late relapses occurred equally frequently regardless of intervention. Compared to pancreas volume before ICI-℞, >20% volume loss occurred in 55% 1 year post-pancreatitis, more so with dual ICI-Rx, regardless of pain or steroid therapy at presentation. 18% had new diabetes within 2 years of pancreatitis. No patient developed calcifications or duct dilation. Conclusion: Type 3 AIP is a novel drug-induced chronic inflammatory disease of the pancreas. Predominantly asymptomatic and mild in severity, it causes rapid pancreatic atrophy and functional endocrine failure despite steroid therapy or ICI-℞ withdrawal. Table 1. - Clinical profile of all type 3 and subjects in imaging cohorts Type 3 AIP* (n=248) Imaging cohort (n=93) Symptomatic (n=94) Asymptomatic (n=154) ≥3x lipase elevation cohort (n=48) 2x lipase elevation cohort (n=24) Normal lipase cohort (n=21) Median Age in years (IQR) 61 (50-68) 62 (54-69) 58 (49-67) 63 (54-69) 59 (55-67) Male N (%) 37 (39%) 72 (47%) 17 (35%) 18 (75%) 13 (62%) Cancer type (%) Genitourinary 27 (29%) 63 (41%) 20 (42%) 14 (58%) 10 (48%) Melanoma 26 (28%) 28 (18%) 16 (33%) 3 (13%) 5 (24%) Other 41 (44%) 63 (41%) 12 (25%) 7 (29%) 6 (29%) ICI Agent (%) CTLA-4 8 (9%) 10 (6%) 5 (10%) 2 (8%) 4 (19%) PD-1 62 (66%) 95 (62%) 28 (58%) 14 (58%) 10 (48%) Combined 24 (26%) 49 (32%) 15 (31%) 8 (33%) 7 (33%) ICI doses prior to elevated lipase (IQR) 4 (2-6) 3 (2-8) 5.5 (3-10) 4.5 (3-13) 3 (2-5, to normal lipase) Median days from ICI to pancreatitis (IQR) 114 (69-264) 113 (52-230) 124 (83-261) 175 (63-348) 95 (47-167, to normal lipase) ICI discontinued (%) 67 (71%) 74 (48%) 28 (58%) 14 (58%) 11 (52%) Risk factors (%) Alcohol consumption 40 (43%) 69 (45%) 22 (46%) 13 (54%) 12 (57%) Smoking history 52 (55%) 77 (50%) 24 (50%) 17 (71%) 7 (33%) Diabetes prior to pancreatitis 16 (17%) 44 (29%) 15 (31%) 6 (25%) 4 (19%) Drug allergy 56 (60%) 81 (53%) 22 (46%) 10 (42%) 10 (48%) Prior history of pancreatitis 5 (5%) 6 (4%) 2 (4%) 1 (4%) 0 *Autoimmune pancreatitis, IQR= interquartile range, ICI= immune checkpoint inhibitor, CTLA-4 (cytotoxic T lymphocyte-associated protein 4), PD-1 (programmed cell death receptor-1) and PD-L1 (programmed cell death ligand-1) Figure 1.: a: Serial pancreatic volume in normal lipase, 2x and 3x groups (median, cm3), b: Serial Pancreatic Volume: Single Agent vs Combination in 3x group (median, cm3), c: Percentage of patients with >20% pancreas volume loss in each group.

Serum differential proteomic profiling of patients with isolated methylmalonic acidemia by iTRAQ.

Isolated methylmalonic acidemia (MMA) is an inherited organic acid metabolic disorder in an autosomal recessive manner, caused by mutations in the methylmalonyl coenzyme A mutase gene, and the isolated MMA patients often suffer from multi-organ damage. The present study aimed to profile the differential proteome of serum between isolated MAA patients and healthy control. The in vivo proteome of isolated MAA patients and healthy subjects was detected by an isobaric tag for relative and absolute quantitation (iTRAQ). A total of 94 differentially expressed proteins (DEPs) were identified between MMA patients and healthy control, including 58 upregulated and 36 downregulated DEPs in MMA patients. Among them, the most significantly upregulated proteins were CRP and immunoglobulins, and the top five most significantly downregulated proteins were all different types of immunoglobulins in MMA patients. GO analysis showed that these DEPs were mainly enriched in immune-related function and membrane protein-related function. KEGG revealed that these DEPs were mainly enriched in lysosome and cholesterol metabolism pathways. Also, these DEPs were predicted to contribute to lipid metabolic diseases. We addressed the proteomes of isolated MMA patients and identified DEPs. Our study expands our current understanding of MMA, and the DEPs could be valuable for designing alternative therapies to alleviate MMA symptoms.

Metastatic bone disease: Early referral for multidisciplinary care.

It is estimated that more than half of all cancers develop bony metastases, exacting a substantial cost in terms of patient quality of life and healthcare expenses. Prompt diagnosis and management have been shown to reduce morbidity and costs. When a patient with a history of cancer presents with musculoskeletal pain, heightened awareness of the risk of bone metastasis should prompt immediate referral to an orthopedic specialist. A multidisciplinary approach is needed to identify an appropriate treatment plan for the patient based on the prognosis, fracture status, and extent of skeletal disease.

Development of an immunohistochemical assay for Siglec-15

Siglec-15, a member of sialic-acid binding immunoglobulin type lectins, is normally expressed by myeloid cells and upregulated in some human cancers and represents a promising new target for immunotherapy. While PD-L1 blockade is an important strategy for immunotherapy, its effectiveness is limited. The expression of Siglec-15 has been demonstrated to be predominantly mutually exclusive to PD-L1 in certain cancer histologies. Thus, there is significant opportunity for Siglec-15 as an immunotherapeutic target for patients that do not respond to PD-1/PD-L1 inhibition. The aim of this study was to prospectively develop an immunohistochemical (IHC) assay for Siglec-15 to be used as a companion diagnostic for future clinical trials. Here, we create and validate an IHC assay with a novel recombinant antibody to the cytoplasmic domain of Siglec-15. To find an enriched target, this antibody was first used in a quantitative fluorescence (QIF) assay to screen a broad range of tumor histologies to determine tumor types where Siglec-15 demonstrated high expression. Based on this and previous data, we focused on development of a chromogenic IHC assay for lung cancer. Then we developed a scoring system for this assay that has high concordance amongst pathologist readers. We then use this chromogenic IHC assay to test the expression of Siglec-15 in two cohorts of NSCLC. We found that this assay shows a higher level of staining in both tumor and immune cells compared to previous QIF assays utilizing a polyclonal antibody. However, similar to that study, only a small percentage of positive Siglec-15 cases showed high expression for PD-L1. This validated assay for Siglec-15 expression may support development of a companion diagnostic assay to enrich for patients expressing the Siglec-15 target for therapy.