All Articles

Deborah J.W. Lee¹, Tar-Choon Aw^1,2,3*

¹Department of Laboratory Medicine, Changi General Hospital, Singapore

²Clinical Senior Lecturer (Medicine), National University of Singapore (NUS) Yong Loo Lin School of Medicine, Singapore

³Clinical Professor (Pathology), Duke-NUS Graduate School of Medicine, Singapore

Heart failure is a major clinical problem affecting 64 million people worldwide with a 5-year mortality rate of around 50%. Patients present to the emergency department with inability to breathe properly. Heart failure is an important condition not to be missed as accurate and early diagnosis or exclusion is crucial for timely intervention. Conventionally heart failure was regarded as congestion consequent to fluid accumulation. Currently heart failure is viewed as a complex heterogeneous entity encompassing severity (clinical versus sub-clinical), onset (acute versus chronic), vascular compartment involved (intra- versus extra-vascular), besides fluid accumulation (cardiopulmonary versus generalized). There is a myriad of biomarkers that reflect different parts of heart failure pathophysiology. However, only natriuretic peptides remain as the “gold standard” against which other biomarkers are compared. This review provides a current update on the utility of natriuretic peptides in clinical practice. We will provide a brief overview of natriuretic peptides, the assays, their clinical use in heart failure, some caveats for their use (age, chronic kidney disease, obesity, heart failure with preserved ejection fraction) and highlight some emerging applications.

Ada Alice Dona^1,2#, James F Sanchez^1#, Joycelynne M Palmer³, Timothy W. Synold⁴, Flavia Chiuppesi⁵, Sandra Thomas², Enrico Caserta^1,2, Mahmoud Singer^1,2, Theophilus Tandoh^1,2, Arnab Chowdhury³, Amrita Krishnan¹, Michael Rosenzweig¹, Don J Diamond⁵, Steven Rosen^1*, Flavia Pichiorri^1,2*, Sanjeet Dadwal^6*

¹Judy and Bernard Briskin Center for Multiple Myeloma Research, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA

²Department of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope, Duarte, CA

³Department of Computational and Quantitative Sciences, Beckman Research Institute, City of Hope, Duarte, CA

⁴Department of Cancer Biology, City of Hope, Duarte, CA

⁵Department of Experimental Therapeutics, City of Hope, Duarte, CA

⁶Department of Medicine, Division of Infectious Disease, City of Hope, Duarte, CA USA

^#These authors contributed equally to this work.

Background: Vaccines for SARS-CoV-2 have been considerably effective in reducing rates of infection and severe COVID-19. However, many patients, especially those who are immunocompromised due to cancer or other factors, as well as individuals who are unable to receive vaccines or are in resource-poor countries, will continue to be at risk for COVID-19. We describe clinical, therapeutic, and immunologic correlatives in two patients with cancer and severe COVID-19 who were treated with leflunomide after failing to respond to standard-of-care comprising remdesivir and dexamethasone. Both patients had breast cancer and were on therapy for the malignancy.

Methods: The protocol is designed with the primary objective to assess the safety and tolerability of leflunomide in treating severe COVID-19 in patients with cancer. Leflunomide dosing consisted of a loading dose of 100 mg daily for the first three days, followed by daily dosing, at the assigned dose level (Dose Level 1: 40 mg, Dose Level -1, 20 mg; Dose Level 2, 60 mg), for an additional 11 days. At defined intervals, serial monitoring of blood samples for toxicity, pharmacokinetics, and immunologic correlative studies were performed, as well as nasopharyngeal swabs for PCR analysis of SARS-CoV-2.

Results: Preclinically, leflunomide impaired viral RNA replication, and clinically, it led to a rapid improvement in the two patients discussed herein. Both patients completely recovered, with minimal toxicities; all adverse events experienced were considered unrelated to leflunomide. Single-cell mass-cytometry analysis showed that leflunomide increased levels of CD8+ cytotoxic and terminal effector T cells and decreased naïve and memory B cells.

Conclusions: With ongoing COVID-19 transmission and occurrence of breakthrough infections in vaccinated individuals, including patients with cancer, therapeutic agents that target both the virus and host inflammatory response would be helpful despite the availability of currently approved anti-viral agents. Furthermore, from an access to care perspective, especially in resource-limited areas, an inexpensive, readily available, effective drug with existing safety data in humans is relevant in the real-world setting.

Salil Chowdhury¹, Daniel Garrido², Dina Halegoua-DeMarzio³, Christopher Roth⁴, Hie-Won Hann^3*

¹Thomas Jefferson University Hospital, Department of Internal Medicine, Philadelphia, PA

²Cooper University Hospital, Digestive Health Institute, Camden, NJ

³Thomas Jefferson University Hospital, Division of Gastroenterology and Hepatology, Philadelphia, PA

⁴Thomas Jefferson University Hospital, Department of Radiology, Philadelphia PA

Hepatocellular Carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide, with chronic hepatitis B virus (HBV) infection being an important risk factor for HCC. While nucleos(t)ide analog (NA) therapy has succeeded in suppressing HBV replication and decreasing the risk of HCC in patients with HBV infection, there remains a persistent risk of HCC in those patients. Furthermore, previous studies have highlighted worse survival in patients who developed HCC while on successful NA therapy compared to those who developed HCC without previous NA treatment.

 We conducted a long-term, retrospective case study in 5 patients observed between 10 and 25 years, to further explore the poor outcomes in patients with HBV-associated HCC with or without previous NA therapy. Our study highlights the aggression and recurrence of HCC in patients with HBV infection, well-suppressed on NA therapy. The results of our observation emphasize the need for early referral for liver transplantation in these select patients.

Marc Roder¹ and Sascha Kahlfuss^1,2,3,4*

¹Institute of Molecular and Clinical Immunology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.

²Institute of Medical Microbiology and Hospital Hygiene, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.

³Health Campus Immunology, Infectiology and Inflammation (GCI³), Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.

⁴ Center for Health and Medical Prevention (CHaMP), Otto-von-Guericke-University, Magdeburg, Germany.

The energy metabolism was demonstrated to directly modulate immune cell function and thereby physiological and detrimental immune responses. In addition, the field of immunometabolism is vastly growing. However, yet there remain fundamental scientific questions in the field, which require the organization of national and international networks as well as the implementation of immunometabolism into curricula, scientific societies, and immunological routine diagnostics to hold the promise of personalized medicine to our patients within the next decade.

Matthew P. Hardy^1*, Tony Rowe¹, and Sandra Wymann²

¹CSL, Bio21 Institute, Victoria, Australia

²CSL, CSL Biological Research Centre, Bern, Switzerland

Human Complement Receptor 1 (CR1/CD35) is a potent negative regulator of the complement system. Its mechanism of action is through interaction with the complement activation fragments, C3b and C4b to mediate decay acceleration of the C3 and C5 convertase complexes as well as cleavage of both ligands into inactive fragments via cofactor activity. The result is inhibition of the classical, lectin, and alternative complement pathways. This article will focus on recombinant soluble forms of CR1 that have been generated as potential therapeutics for complement-mediated disorders. Specifically, we will review and contrast the in vitro and in vivo properties of: sCR1 (BRL55730/TP10/CDX-1135), the soluble full-length extracellular domain of human CR1; sCR1-sLe^x (TP20), a glyco-engineered version of sCR1 additionally targeted to activated endothelium; APT070 (Mirococept), a CR1 fragment conjugated to a myristoylated peptide to enhance tissue targeting; and CSL040, a soluble truncated version of the CR1 extracellular domain which exhibits altered potency and pharmacokinetic properties as compared to the parental molecule. The data obtained from studies on the effects of these CR1-based molecules in animal models of disease and their therapeutic applications will also be discussed.

Kushal Gandhi^1#, Nathan Joshua Manales^1#, Asley Sanchez^1#, Srikanth Mukkera^1*, Anusha Ammu¹, Janine Klar¹, Alex Gibson¹, Evangelina Santiago², Ailena Mulkey², Jammie Holland², Maneesh Mannem¹, Lakshmi P. Alahari¹, and John Garza^1,3

¹ School of Medicine, Texas Tech University Health Sciences Center (TTUHSC) at the Permian Basin, TX, USA

² Clinical Research institute at the Permian Basin, Texas Tech University Health Sciences Center – Permian Basin, TX, USA

³ The University of Texas Permian Basin, Odessa, TX, USA

^# Authors contributed equally

Background: In the spring of 2021, coronavirus disease 2019 (COVID-19) vaccines were approved and distributed in the United States for the public to combat the COVID-19 pandemic, but their rapid development leaves some questions unanswered. Vaccine efficacy has always been a point of interest for individuals with rheumatological diseases that take immunosuppressants. This study investigates the vaccine efficacy of two COVID-19 mRNA-based vaccines, Moderna and Pfizer, in subjects in West Texas patients with autoimmune diseases.

Materials and Methods: Blood was collected from Texas Tech University employees who received both doses of COVID-19 vaccines within the past nine months. Subjects were separated into either a group with a known history of rheumatic disease (n=18) or those without (n=18). The samples were analyzed for serum immunoglobulin A (IgA), immunoglobulin G (IgG), and immunoglobulin M (IgM) levels using specific enzyme-linked immunoassay kits, and a neutralizing antibody test using a surrogate virus was conducted as well. Results were analyzed using the Mann-Whitney U test (unpaired, two-tailed).

Results: There was no significant difference in serum IgG and IgA levels between the control and rheumatologic disease groups, but there were significant differences in serum IgM levels. All subjects cleared the threshold for the neutralizing antibody test.

Conclusion: The relatively similar serum IgG levels and the 100% detection rate of effective neutralizing antibodies across both groups indicate promising signs of serological response for subjects with autoimmune conditions, but the relatively low serum IgA and IgM levels of the study the group warrants further investigation.

Baofa Yu, MD^1,2,3,4*, Qiang Fu, MS³, Yan Han, MS³, Jian Zhang³, Dong Chen，MD³

¹Immuno Oncology Systems, Inc., San Diego, CA 92122, USA

²TaiMei Baofa Cancer hospital, Dongping, Shandong Province, China, 271500

³Jinan Baofa Cancer hospital, Jinan, Shandong Province, China，250000

⁴Beijing Baofa Cancer Hospital, Beijing, China

Aim: To study the immunity reaction in tumor by intratumoral injection with a drug PYM and DNP, where it produces abscopal effect by the expression of immunological genes of tumor on home side (left side) while it brings a similar expression of same genes in tumor on opposite side (right side) of mice.

Method: Prepare each tumor on left side of 6 mice and injected intratumoral with a PYM+DNP and PYM control on day 1 and 7. Two day later of day 1, one of groups mice were inoculated with 0.2ml of H22 cells (10⁵/ml) again on the right underarms as opposite side for controls. On day15, the tumor on bilateral sides were excised for qPCR measurement.

Result: It showed that inflammation with the expression of the CoL1a1, CD4, IL12aÂ, TGFb1Â, Elastin, Elastin, Cox2, CD11b/c, CD8, TNFa in different groups; The inflammation in both side of tumor but these is not only a increasing expression of Collal, CD4, IL12aÂ, TGFb1Â, Elastin, NFKB, Cox2, CD11c, CD8 and TNFa in tumor on home side of mice treated with PYM+DNP but also a similar an increasing expression of same genes in tumor on opposite side of mice which not treated at all. In the control group, it showed that inflammation without an expression of all factors related above immunity genes in both tumor on home treated with PYM only and opposite side of mice which not treated at all.

Conclusion: It indicated that PYM and hapten of DNP can induce an inflammation with stimulation of immunity reaction with the expression of the CoL1a1, CD4, IL12aÂ, TGFb1Â, Elastin, Elastin, Cox2, CD11b/c, CD8, TNFaÂ, which resulted in an abscopale effect. PYM can induce an inflammation but without expression of immuno genes, therefore, hapten is playing an important role with PYM in the special immunity reaction.

Lisa M. James^1,2,3, Apostolos P. Georgopoulos^1,2,3,4*

¹The HLA Research Group, Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN, 55417, USA

²Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA

³Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN 55455, USA

⁴Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA

The association of Human Leukocyte Antigen (HLA) with melanoma has been well documented. Similarly, the outcome of checkpoint blockade immunotherapy (CBI) in melanoma depends, to some extent, on the HLA genotype of the patient. Although specific favorable (or unfavorable) HLA alleles for CBI outcome for melanoma have been identified, there is currently no reliable way to predict a positive, neutral or negative melanoma CBI outcome for other alleles. Here we used an immunogenetic epidemiological approach to identify HLA alleles whose frequency is negatively (or positively) associated with melanoma prevalence (protective or susceptibility alleles, respectively). The findings demonstrated that, indeed, HLA alleles that are negatively associated with melanoma prevalence in the population have been associated with good CBI outcome at the individual level and, conversely, HLA alleles that are positively associated with melanoma prevalence have been associated with poor CBI outcome in individuals. Given this good prediction of CBI cancer immunotherapy by specific immunogenetically discovered HLA alleles, we used this epidemiologic immunogenetic approach to identify more HLA Class I and II alleles protective (or susceptibility) for melanoma which would thus be good predictors of CBI outcomes in those cancers. This is a new approach to successfully (a) identify HLA protective or susceptibility alleles for melanoma, and (b) use that information in anticipating outcomes in CBI cancer immunotherapy.

Gavin Yuen*, Saundarai Bhanot^#, Jeremy Steen, Minahil Syed, Austin Mardon^#

Sharpen the Quill, Ontario, Canada

Vaccination is a powerful inducer of immunity against SARS-CoV-2 and its recent variants. However, it is important to expand the defensive repertoire against this virus as vaccination is not always efficacious or accessible to everyone. Protein therapeutics in the form of monoclonal antibodies have been used to neutralize the Spike protein, but their efficacy has been limited with rapidly evolving mutations. Cocktail antibodies have been used to combat antigenic escape through diversifying antigen recognition and the overall neutralization capacity. However, the production of cocktail antibodies can be costly and requires a high dosage to achieve the desired therapeutic effect. Alternatively, bispecific antibodies have been used, which contain two recognition specificities within the same molecule. This effectively reduces the cost of production and dosage required to achieve a target therapeutic effect. Bispecific antibodies were reported to bind SARS-CoV-2 antigen with nanomolar affinities. The neutralization potentials (IC50 values) within the same studies were generally more efficacious than their cocktail antibody counterparts. Some studies showed that bispecific antibodies could also confer additional neutralization effector functions, such as recruiting the complement system. Although the recognition of variants was diverse, to our knowledge, there is no data to suggest that bispecific antibodies have a broader recognition of variant strains than cocktail antibodies. Future studies should aim to explore the clinical benefits of bispecific antibodies for SARS-CoV-2 and the emerging variant strains to better understand its benefits in treatment.

Apostolos P. Georgopoulos^1,2,3,4*, Lisa M. James^1,2,3

¹The HLA Research Group, Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN, 55417, USA

²Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA

³Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN 55455, USA

⁴Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA

Human leukocyte antigen (HLA) genes have been associated with susceptibility and protection against a number of cancers. Here we used an immunogenetic epidemiological approach to evaluate the overall influence of 127 HLA Class I and II alleles on 30 types of cancer. We found a preponderance of protective alleles (negatively correlated with cancer prevalences), especially for HLA Class I. Of the 30 cancers investigated, 13 were associated with mostly protective HLA effects whereas only 2 were associated with mostly susceptibility HLA alleles. Taken together, these findings highlight the broad influence of HLA on cancer and the complexity of HLA-cancer associations.­­

Raquel García-Belmonte, Daniel Pérez-Núñez, Yolanda Revilla^*

Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Microbes in Health and Welfare Department, c/ Nicolás Cabrera, 1, 28049 Madrid, Spain

Yuxi Yan^1#, Quan Zhao^1#, Ya Huang¹, Janine Y. Yang², Jie Zou¹, Chunxia Ao¹, Xiaojuan Chai¹, Renhong Tang¹ and WenQing Yang^1*

¹State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Pharmaceutical Co., Ltd., Nanjing, Jiangsu, China.

²Massachusetts Eye and Ear, Harvard Medical School, USA

Background and objective

Experimental autoimmune encephalomyelitis (EAE) is the most commonly used model for studying autoimmune-mediated myelin degradation in multiple sclerosis (MS). Here, we evaluated the pharmacologic responses of several anti-inflammatory drugs with varying mechanisms of actions (MOAs) using EAE models induced by different MOG immunogens to reveal differential pharmacologic characteristics of the disease models and provide a general guidance in animal model selection for MS research.

Methods

The pharmacologic responses of anti-inflammatory drugs with different mechanisms of actions (MOAs) were evaluated using EAE models induced by either myelin oligodendrocyte glycoprotein p35-55 (MOG_35-55)  or p1-128 (MOG_1-128). EAE animal models were developed in mice with C57BL/6 background. The animals were treated with different anti-MS medications, including 3 B cell-mediated agents and 2 T cell-mediated agents, respectively. Clinical symptoms were monitored and scored, and pharmacodynamic markers including cytokine secretion, inflammatory cell infiltration, and demyelination in spinal cord were analyzed.

Results

In MOG_35-55 peptide-induced EAE model, T cell modulating agents Secukinumab and Fingolimod significantly alleviated clinical symptoms, while B cell-depleting agents, BTK inhibitors PRN2246 and Telitacicept, displayed minimal therapeutic effects or even exacerbated disease progression. In contrast, both T cell-modulating agents and B cell-depleting agents ameliorated disease severity in MOG_1-128-induced EAE model. T cell and B cell infiltration in spinal cord increased with disease progression in MOG_1-128-induced EAE model.

Conclusions

Our results demonstrated that induction of EAE by different myelin antigens resulted in differential pharmacologic responses to drugs with specific MOAs. The MOG_35-55 peptide-induced EAE model only responded to T cell-modulating drugs, whereas the MOG_1-128 protein-induced EAE model exhibited therapeutic sensitivity to both T cell- and B cell-modulating agents. These data suggest the MOG_35-55 peptide-induced EAE model is suitable for assessing T cell-modulating agents while MOG_1-128 protein-induced model can be employed to evaluate both T cell- and B cell-modulating agents.

Dave M. Mathew BS, Kathryn S. Varghese BS, Serena M. Mathew, Roshan Pandey, Sarah Ahmed, Stephanie A. Salazar BS, Dillon O. Rogando BS, Peter J. Fusco BS, Kenneth H. Levy BS, Adham Ahmed BS*

City University of New York (CUNY) School of Medicine, New York, New York

Jin Hyang Kim^1,2#, Grace Park³, Bhavna Paratala^1,4, Rene Rijnbrand^1,5, Michael J. Sofia¹ and Hie-Won Hann^3*

¹Arbutus Biopharma Corporation, 701 Veterans Circle, Warminster, Pennsylvania, 18974, US

²Current address: Bristol Myers Squibb, 3401 Princeton Pike, Lawrenceville, NJ 08648, US

³Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, US

⁴Current address: Adaptimmune LLC, 351 Rouse Boulevard, Philadelphia, PA 19112, US

⁵Current address: Dicerna Pharmaceuticals, 33 Hayden Ave, Lexington, MA 02421

Hepatitis B virus (HBV) is a main cause of hepatocellular carcinoma (HCC) development. Although controversial, it is increasingly recognized that the immune responses directed against infected hepatocytes drive hepatic inflammation and tissue injury. Here we extended our previous findings to report that serum surface antigen (HBsAg) levels are a biomarker not only for HBV-specific immunity, but also for ongoing non-specific immune activation. We found that the HBV-specific T cell responses in patients with HBsAg < 500 IU/mL, while significantly higher than those in patients with HBsAg > 50,000 IU/mL, had already reached levels comparable to patients with seroclearance. In addition, lower HBsAg levels were associated with reduced non-specific immune activation, while no further reduction was observed with HBsAg < 500 IU/mL. We propose HBsAg is a therapeutic target for reducing inflammation.

Paul F. Cotter

Cotter Laboratory, Arlington, MA, 02476, USA

The aim is to describe the array of plasmacytes (PC), cells known as the source of antibody, occurring in the bone marrow (BM) of lame ducklings. The method is by a light microscopic examination of touch preparation slides made from femur samples and stained with Wright-Giemsa. Samples were obtained on site at commercial farms where slide preparations were made; reducing the possibility that observations are technical artifacts.

The results: indicate that PC occur in a multitude of sizes, shapes, nuclear/cytoplasmic (N/C) ratios, ploidy, and nuclear and cytoplasmic conditions. Normal PC are illustrated first, followed by atypical forms. Some PC are presented in the context of neighboring BM cells of the granulocyte, erythrocyte, and reticulum cell (histiocyte) series.

More than 100 Mott-type PC were measured in a single sample from a 13-day lame duck; and several distinct forms were identified. Size, as measured by their longest axis, varied from 6.1 to 28 μm and it appears to be normally distributed. Moreover, N/C ratios were distributed across a three-fold range (0.3 – 0.9) indicating Mott phenotypes can occur at multiple developmental stages. Motts differed in Russell Body (RB) size, and nuclear condition. A novel Mott type, “orb” form, with partially lysed nuclei is also described.

PC were often found in association with giant granulated histiocytes (ggh) and non-granulated giant histiocytes (gh). Other atypical forms are “hand-mirror” PC, trinucleate and binucleate PC resembling cells seen in multiple myeloma (MM) and lymphomas.

 Collectively these PC variants constitute “reactive plasmatosis” (RP) likely arising as a consequence of the presence of various bacteria including Streptococcus and E. coli.            

The conclusions: It is demonstrated that RP as occurs in lame ducklings suffering from bacterial infections, provides a unique theater for the study of PC variability. Atypical PC, some resembling neoplastic types, were common in RP BM. The significance of the study relates to the importance of PC in disease and immunity; therefore, these observations should interest those who specialize in these areas. They expand the knowledge of avian plasmacyte morphology.

Nicholas Noverati¹, Daniel Garrido^1,2, Dina Halegoua-DeMarzio^1,2, Hie-Won Hann^1,2,3*

¹Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107 USA

²Division of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA 19107

³Liver Disease Prevention Center, Thomas Jefferson University Hospital, Philadelphia, PA 19107 USA

Introduction: Chronic hepatitis B virus (HBV) infection is prevalent worldwide and up to 40% is known to progress to serious complications including cirrhosis and hepatocellular carcinoma (HCC). The outcome of the remaining infected individuals is not well documented. Our case series describes a longer cohort of chronic HBV infections that have remained asymptomatic with no progression of liver disease.

Case Series: Thirty-three patients (ages 31-84) with chronic HBV infection were identified. All patients had no significant elevations in transaminase levels and were followed over 32 years, collectively. 18/33 had a fluctuating greater magnitude of HBV viral load with no elevations in tumor marker or significant radiographic changes to their liver.

Discussion/Conclusion: Chronic HBV infection can lead to serious complications over time, the mechanism of which are not well understood. The variation in patients that do and do not develop these complications stresses the importance of the individual response to the virus and may highlight host immune response differences.

Spyros A. Charonis^1,2, Apostolos P. Georgopoulos^1,2*

¹The HLA SARS-CoV-2 Research Group, Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN 55417, USA

²Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA

Paul F. Cotter

Cotter Laboratory, Arlington, MA 02476, USA

The aim is to demonstrate a variety of apoptotic heterophils (equivalents of mammalian neutrophils) occurring in hemograms of 50 apparently healthy pullets housed in cages. These atypical cells are found in blood with normal total white cell levels (TWBC, ~20K) and in those ranging up to 100(K) a leukocytosis/leukemoid reaction level. Conversely heterophil/lymphocyte (H/L) ratios in all hens ranged between 0.14 – 0.50 (homeostasis). The Arneth index (a heterophil age measure) of 1.8 computed using only intact heterophils indicated a “left-shift”, suggesting inflammation even in the context of a normal hemogram.

The results: atypical heterophils with condensed (pyknotic) and fragmented nuclei (karyorrhexis), ruffled cytoplasmic membranes (zeiosis), apoptotic body formation, and other characteristics of apoptosis circulated in the blood of the study hens. Highly unusual cells as a monocyte containing a phagocytosed apoptotic body composed of heterophil granules, and a Mott cell (atypical plasmacyte) were also found.

More importantly, heterophils displaying thin, swollen and externalized nuclei suggestive of an unusual form of karyolysis were present. These cells were often seen in the company of free or RBC associated bacteria and fungi. There were also two examples of bacteria phagocytosed by apoptotic cells.

Other types of apoptotic cells were in 16/50 (32%) of hens from the study sample. These included small and medium size lymphocytes, monocytes, and metamyelocytes. Frank evidence of bacteremia (5/50, 10%) fungemia (4/50, 8%) and both (1/50, 2%) were detected. This suggests a relation between hematological atypia and the presence of circulating microorganisms possibly mediated through the release of toxins. Atypia of the circulation are sentinels, an alert to investigators or clinicians who are interested in the relation between the composition of blood and stress measurement or disease.

Conclusions: these observations apply to apparent morphologic plasticity of the heterophil, its role in the innate immune system, and its use in determining stress. In the cases described here the initial computation of the H/L ratios suggested the absence of stress. Moreover, this occurred in the context of either a normal or a high TWBC. However, heterophil age indicated a left-shift; a population predominated by young cells. This situation occurs when there is a demand to replace cells that have left the circulation either due to inflamed tissues or to death while circulating. Therefore, circulating apoptotic cells suggest stress even when the H/L is low and the TWBC is normal.

Kerstin S. Baun¹, Nathan T. Kearns², Jennifer K. Peterson¹, John M. Miguelez¹

¹Clinical Services, Advanced Arm Dynamics, Redondo Beach, CA, USA

²Department of Psychology, University of North Texas, Denton, TX, USA

Abstract

Purpose: 

To develop and psychometrically evaluate the Comprehensive Arm Prosthesis and Rehabilitation Outcomes Questionnaire (CAPROQ), a 28-item, self-report measure of three key facets associated with successful rehabilitation (perceived function, satisfaction, and pain) designed specifically for the adult upper limb loss (ULL) population.

Materials and Methods:

Using a national sample of adult ULL patients (N=240), factor structure, internal consistency, convergent/concurrent validity, and known group validity of the total CAPROQ score and three subscale scores were evaluated.

Results:

Confirmatory factor analysis indicated adequate-to-strong factor loading on each subscale: satisfaction (.623-.913), perceived function (.572-.860) and pain (.422-.834).  Internal consistencies for the total measure and measure subscales were good-to-excellent (.89-.95) and convergent validity indicated moderate-to-strong statistically significant associations between the CAPROQ subscales and relevant measures. Concurrent validity showed moderate associations between CAPROQ total score, prosthetic wear time, and psychosocial adjustment scores. Known group validity indicated significant differences on CAPROQ total score between initial and definitive fitting stages (p=.012).

Conclusion:

Psychometric evaluation indicated that the CAPROQ and CAPROQ subscales were structurally sound, internally consistent, and demonstrated convergent validity with currently used assessments of perceived functioning, satisfaction, and pain.  CAPROQ is needed for guiding individual patient care, improving care models and future prosthesis selection and development.

Lisa M. James^1,2,3, Apostolos P. Georgopoulos^1,2,3,4*

¹The HLA Research Group, Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN, 55417, USA

²Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA

³Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN 55455, USA

⁴Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA

Human leukocyte antigen (HLA) is widely recognized to influence individual Type 1 diabetes (T1D) risk. Here we utilized an immunogenetic epidemiological approach to evaluate the influence of HLA on T1D at the population level. Specifically, we evaluated the correlations between the population frequencies of 127 HLA Class I and II alleles and the population prevalence of T1D in 14 Continental Western European countries to identify a population-level HLA profile for T1D. The results of these analyses generally corroborated prior findings regarding the influence of HLA on T1D risk and protection and revealed several novel HLA-T1D associations. The findings, discussed within the context of the role of HLA in pathogen elimination and autoimmunity, point to a contributory role of exposure to pathogens in the absence of protective HLA in underlying the autoimmune destruction of pancreatic beta cells in T1D.

Lisa M. James^1,2,3, Apostolos P. Georgopoulos^1,2,3,4*

¹The HLA Research Group, Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN, 55417, USA

²Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA

³Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN 55455, USA

⁴Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA

Very few studies have evaluated associations of human leukocyte antigen (HLA) with motor neuron diseases (MND). Using an immunogenetic epidemiological approach, we identified a population-level HLA profile for MND by evaluating the correlations between the population frequencies of 127 HLA Class I and II alleles and the population prevalence of MND in 14 Continental Western European countries. The results demonstrated that significantly more HLA alleles, particularly for Class I, were negatively associated with the population prevalence of MND, suggesting a preponderance of protective vs susceptibility effects. The findings add to the limited literature implicating HLA in MND and considering the role of HLA in immune system responses to pathogens, suggest a potential influence of pathogens in MND.

Fernanda Pinto-Mariz^*, Ekaterini Goudouris²

IPPMG-Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil

Inborn errors of immunity (IEI) are a heterogeneous group of more than 400 diseases, mostly genetically determined, whose main clinical manifestations are severe and / or recurrent infections. Despite the efforts of immunology societies worldwide, this group of diseases remains underdiagnosed. The present review attempts to describe, and call the attention of the physicians, for the infectious and non-infectious manifestations related to IEI. The main clinical manifestations, as well as others that are not so frequent, have been reported in this manuscript. In order to facilitate clinical reasoning, we created a table to illustrated some of them and subdivided the main manifestations into infectious, infectious associated with immune dysregulation, only related to dysregulation and others. The dissemination of knowledge about clinical manifestations, especially non-infectious ones, can contribute to early diagnosis of IEI and, consequently, to the reduction of their morbidity and mortality.

Lisa M. James^1,2,3, Spyros A. Charonis^1,2, Apostolos P. Georgopoulos^1,2,3,4*

¹The HLA Research Group, Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN, 55417, USA

²Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA

³Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN 55455, USA

⁴Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA

Human leukocyte antigen (HLA), the most highly polymorphic region of the human genome, is increasingly recognized as an important genetic contributor to dementia risk and resilience. HLA is involved in protection against foreign antigens including human herpes viruses (HHV), which have been widely implicated in dementia. Here we used an in silico approach¹ to determine binding affinities of glycoproteins from 9 human herpes virus (HHV) strains to 113 HLA alleles, and to examine the association of a previously identified HLA-dementia risk profile² to those affinities. We found a highly significant correlation between high binding affinities of HLA alleles to HHV 3 and 7 and the dementia risk scores of those alleles, such that the higher the estimated binding affinity, the lower the dementia risk score. These findings suggest that protection conferred by HLA alleles may be related to their ability to bind and eliminate HHV3 and HHV7 and point to the possibility that protection against these viruses may reduce dementia incidence.

Darshna Yagnik*

Middlesex University, Department of Natural Sciences, School of Science and Technology, The Burroughs, London, NW4 4BT, UK

The immune response to SARS-CoV-2 varies from asymptomatic or mild symptoms of high temperature, muscle aches and coughs lasting 7 to 14 days to lower respiratory tract infections leading to pneumonia and serious respiratory distress as well as long COVID-19. Complications occur due to an abnormal immune response which involves upregulation of multiple cytokines leading to sustained inflammation which results in the spread of infection to vital organs. The double vaccine roll out has been rapid however vaccine mediated antibodies are not 100% effective against future coronavirus variants which may become increasingly more resistant and easily transmissible to overcome host immunity. Invariably supportive therapies will be needed. Research has shown that coenzyme Q10 and vitamin D deficiencies can have detrimental effects on immune cell defence, function and cytokine secretion promoting inflammation and sepsis especially against microbes. Early interventions including supplementation of these factors could mitigate cellular dysfunction especially in relation to mitochondria bioenergetics and help maintain cell immunity. This is particularly important as chronically ill COVID-19 patients seem to display abnormal immune cell phenotypes in infected organs indicating this could contribute to disease progression. The immune response and proposed roles of Vitamin D and Coenzyme Q10 in COVID-19 are discussed.

Nick F. Hallam^*

Colposcopy Clinic, Women's Outpatients, Cumberland Infirmary, Carlisle, England, United Kingdom

This short communication reports additional research that extends the previously published article - Commentary: HPV Catch-Up Vaccination Reduces the Prevalence of HPV 16 and 18 Infections and Cervical Disease: A Retrospective Study.1 One limitation of that study was uncertainty as to whether the catch-up cohort had actually received HPV (human papillomavirus) vaccination. That information has now been obtained. 87 (59%) of the 147 patients in the catch-up cohort had received at least one dose of HPV bivalent vaccine. 69 of these (representing 79% of those vaccinated) had received three doses (as recommended at the time). Both the vaccinated and unvaccinated subsets of the catch-up cohort show a significant reduction in the prevalence of HPV 16 and/or 18 (with/without other high-risk types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68) and of high grade cervical disease compared to an earlier unvaccinated cohort. These results confirm the efficacy of HPV catch-up vaccination and the existence of herd immunity following the introduction of national HPV vaccination campaigns. However, 34 patients (23%) in the catch-up cohort had high grade disease (cervical intraepithelial neoplasia [CIN] 2 or worse), 16 of whom had been vaccinated (12 with three doses, one with two doses and three with one dose of HPV bivalent vaccine) and four of those vaccinated had HPV 16 and/or 18 (with/without other high-risk types), the rest had other HPV high risk types. This emphasises the importance of maintaining cervical screening alongside HPV vaccination.