Intraepithelial lymphocytes (IELs) are abundant in the intestinal epithelium, where they maintain barrier integrity and provide immune defense. Because of their potent cytotoxic and effector potential, IEL activity must be tightly controlled to prevent tissue damage. However, the mechanisms that calibrate IEL responsiveness remain unclear. Here, we identify glucosaminyl (N-acetyl) transferase 2 (Gcnt2) as a key restrainer of both natural and induced gut IEL. Among T cells, Gcnt2 is uniquely enriched in the intestine and partly dependent on retinoic acid signaling. GCNT2-mediated branched glycosylation marks IELs with signatures of tissue adaptation and reduced TCR responsiveness. Genetic ablation of Gcnt2 enhanced IEL degranulation, cytokine production, and cytotoxicity upon stimulation, improving bacterial clearance and limiting infection-induced disease, yet predisposing mice to intestinal inflammation. Mechanistically, GCNT2-mediated glycosylation of CD45 reduced its phosphatase activity, thereby dampening TCR signaling and effector responses. Together, these findings reveal GCNT2 as a glycosylation-dependent checkpoint that fine-tunes IEL effector functions, uncovering a novel mechanism by which the intestinal immune system balances responsiveness and tolerance. ### Competing Interest Statement The authors have declared no competing interest. Eccellenza Professorial Fellowship by the Swiss National Science Foundation, PCEFP3_187018 Helmut Horten Stiftung Swiss National Science Foundation, TMSGI3_211235 ARC DECRA Fellowship, 503658 NHMRC Leadership Investigator Fellowship, GNT2034209 ERC Advanced Grant ‘GlycoCAR’ Fund for Scientific Research-Flanders, FWO, G050420N

Phosphodiesterase (PDE) inhibitors are a class of pharmacological agents that regulate immune and vascular function by controlling the intracellular concentration of key second messengers. By modulating cyclic nucleotide signaling, particularly cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), PDE inhibitors exert pleiotropic effects on vascular tone, immune cell activation, and fibrotic remodeling. Dysregulation of cAMP- and cGMP-dependent pathways contributes to endothelial dysfunction, chronic inflammation, and tissue remodeling in autoimmune, fibrotic, and neurodegenerative diseases. In rheumatology, PDE3, PDE4, and PDE5 isoforms are of particular translational relevance. PDE3 inhibitors improve vasodilation and platelet regulation; PDE5 inhibitors enhance endothelial NO-cGMP signaling and are clinically established in pulmonary arterial hypertension and digital vasculopathy; while PDE4 inhibition suppresses cytokine-driven immune activation by reducing the production of pro-inflammatory mediators, contributing to therapeutic efficacy in conditions such as psoriasis, psoriatic arthritis, and connective tissue disease-associated interstitial lung disease (CTD-ILD). Emerging PDE-targeted agents, including ibudilast and the PDE4B-selective inhibitor nerandomilast, combine immunomodulatory and antifibrotic properties. These compounds have demonstrated clinical benefit and improved tolerability in patients with progressive fibrotic lung disease, highlighting the therapeutic potential of isoform-selective PDE inhibition. Collectively, targeting the NO-cGMP-cAMP signaling axis provides a unifying mechanistic framework for the treatment of vascular, immune, and fibrotic manifestations of rheumatic disease, positioning PDE inhibition as an emerging pillar of modern translational rheumatology.

We identified sialophorin CD43 as a regulator of BCR signaling thresholds. Here, we investigated the role of CD43 in T-cell mediated antibody-secreting cell (ASC) differentiation. CD43 Ab-targeting thwarted BCR signals and proliferation, induced cell death and inhibited ASC-differentiation. CRISPR/Cas9 knockdown of CD43 in this primary B cell system confirmed ASC inhibition emphasizing the role of CD43 in B-cell effector differentiation. CD43-targeting on differentiated ASCs induced rapid apoptosis preceded by diminished Ab-production and XBP1s expression, indicating involvement of the unfolded protein response (UPR). Short-term CD43 targeting revealed Akt1-dependent transcriptional inhibibition of BLIMP1, a known regulator of the UPR in ASCs. CD43 targeting did not affect IRF4 expression, a canonical BLIMP1 transcription factor. We therefore searched for IRF4 post-translational modifications and found that BLIMP1 transcriptional regulation depended on histone deacetylase 11, known to enhance IRF4 binding to the PRDM1 (BLIMP1) promoter. This suggests that CD43-mediated BLIMP1 transcriptional regulation could rely on curbed IRF4 deacetylation reducing its binding to the PRDM1 promoter, modulating BLIMP1 and XBP1s expression and the UPR. We introduce a novel CD43-regulated pathway essential for ASC-differentiation and fitness that can be utilized therapeutically. Supported by South-Eastern Norway Regional Health Authority (Helse Sør-Øst) project number 2021066 and 2023022. Immune Response Regulation: Molecular Mechanisms (IRM)

Review The Role of Biomarkers in the the Pathogenesis, Clinical Manifestations, and Therapeutic Outcome of Systemic Sclerosis Anna Bazsó 1,*, Péter Szodoray 2, Yehuda Shoenfeld 3,4 and Emese Virág Kiss Med Dsci 1,5 1 Department of Clinical Immunology, Adult and Paediatric Rheumatology, Department of Rheumatology and Immunology, Semmelweis University, 1023 Budapest, Hungary 2 Department of Immunology, Oslo University Hospital, Rikshospitalet and University of Oslo, 0372 Oslo, Norway 3 Recanati Medical School, Reichman University, 4610101, Herzelia, Israel 4 Zabludowicz Center for Autoimmune Diseases (Founder), Sheba Medical Center, 5265601 Tel-Hashomer, Israel 5 Division of Locomotor System and Rheumatology Prevention, Department of Internal Medicine and Haematology, Semmelweis University, 1088 Budapest, Hungary * Correspondence: bazsoanna@yahoo.com Received: 12 January 2025; Revised: 20 March 2025; Accepted: 28 March 2025; Published: 3 April 2025 Abstract: Systemic sclerosis (SSc) is a complex autoimmune disorder characterized by progressive fibrosis and obliterative vasculopathy affecting the skin and various internal organs, including the kidneys, lungs, cardiovascular system, and gastrointestinal tract. The disease manifests in two major clinical subtypes: limited cutaneous systemic sclerosis (lcSSc) and diffuse cutaneous systemic sclerosis (dcSSc), distinguished primarily by the extent of skin involvement and the pattern of internal organ involvement. Biomarkers, serving as quantifiable indicators of biological processes in SSc, hold significant potential for refining disease classification, predicting progression, assessing therapeutic responses, and evaluating clinical outcomes. Unlike other autoimmune diseases, SSc lacks highly specific biomarkers. Given its heterogeneity and multifactorial pathogenesis, the development of a composite biomarker panel may represent the most effective approach for future diagnostic and longitudinal monitoring strategies in SSc.

Systemic sclerosis (SSc) is a progressive autoimmune disorder that mainly affects the skin. There are other clinical manifestations as renal, pulmonary, cardiovascular, and gastrointestinal tract involvements. Based on the skin involvement there are two subtypes of SSc, as limited cutaneous SSc (lSSc) which involves the acral part of the body and diffuse cutaneous SSc (dSSc) resulting in significant skin thickening of the body. Despite of the extensive research the pathomechanism is not fully clarified, how Ssc develops, moreover identifying biomarkers to predict the clinical outcome and prognosis still remains challenging. Circulating biomarkers can be crucial to define the diagnosis, to predict the prognosis and monitor the clinical course. However, only some patients are responsive to the therapy in SSc, and there is a need to reach the ideal therapy for any individual to prevent or slow down the progression in early stages of the disease. In this narrative review, our purpose was to summarize the potential biomarkers in Ssc, describe their role in the diagnosis, pathomechanism, clinical course, organ manifestations, as well as the response to the therapy. Biomarkers assessment aids in the evaluation of disease progression, and disease outcome.

BACKGROUND:B-cell acute lymphoblastic leukemia (B-ALL) is classified into subgroups based on known driver oncogenes and molecular lesions, including translocations and recurrent mutations. However, the current diagnostic tests do not identify subtypes or oncogenic lesions for all B-ALL samples, creating a heterogeneous B-ALL group of unknown subtypes.METHODS:We sorted primary adult B-ALL cells and performed transcriptome analysis by bulk RNA sequencing (RNA-seq).RESULTS:Transcriptomic analysis of an adult B-ALL cohort allowed the classification of four patient samples with subtypes that were not previously revealed by standard gene panels. The leukemia of two patients were of the DUX4 subtype and two were CRLF2+ Ph-like B-ALL. Furthermore, single nucleotide variant analysis detected the oncogenic NRAS-G12D, KRAS-G12D, and KRAS-G13D mutations in three of the patient samples, presenting targetable mutations. Additional oncogenic variants and gene fusions were uncovered, as well as multiple variants in the PDE4DIP gene across five of the patient samples.CONCLUSION:We demonstrate that RNA-seq is an effective tool for precision medicine in B-ALL by providing comprehensive molecular profiling of leukemia cells, identifying subtype and oncogenic lesions, and stratifying patients for appropriate therapy.

Chronic lymphocytic leukemia (CLL) growth is dependent on both B cell receptor (BCR) signaling and signals from microenvironmental T helper (Th) cells. We previously described a mechanism where Th cells enhance BCR signaling and proliferation through CD45 phosphatase activity regulation via galectin-1 and CD43. The CLL negative prognostic indicator CD38 is linked to BCR signaling and proliferation, with its expression induced by Th cells. Here, we explore a link between CD38 and CD45 phosphatase activity regulation using patient-derived material in a Th-CLL cell co-culture model. Results demonstrate CD43 and galectin-1 are co-expressed with CD38, defining proliferative CLL cells with augmented CD45 activity. CD38 enzymatic and receptor inhibition regulated CD43 and galectin-1 expression, CD45 activityhi populations, and CLL proliferation, while leaving Th cells largely unaffected. Mechanistically, CD38- or LGALS1 (galectin-1)-deficient malignant B cell lines further confirmed CD38-mediated regulation of CD45 activity and BCR signaling through CD43 expression and galectin-1 surface binding, while galectin-1 contributed to CD43/CD45 colocalization. Together, this highlights CD38 as an important regulator of CD45 activity via CD43 and galectin-1, in turn acting as a positive modulator of CLL proliferation. Ultimately, the CD38/CD45 molecular hub could be an important therapeutic target in CLL.

T cells depend on the phosphatase CD45 to initiate T cell receptor signaling. Although the critical role of CD45 in T cells is established, the mechanisms controlling function and localization in the membrane are not well understood. Moreover, the regulation of specific CD45 isoforms in T cell signaling remains unresolved. By using unbiased mass spectrometry, we identify the tetraspanin CD53 as a partner of CD45 and show that CD53 controls CD45 function and T cell activation. CD53-negative T cells (Cd53(-/-)) exhibit substantial proliferation defects, and Cd53(-/-) mice show impaired tumor rejection and reduced IFNg-producing T cells compared with wild-type mice. Investigation into the mechanism reveals that CD53 is required for CD45RO expression and mobility. In addition, CD53 is shown to stabilize CD45 on the membrane and is required for optimal phosphatase activity and subsequent Lck activation. Together, our findings reveal CD53 as a regulator of CD45 activity required for T cell immunity.

Growing evidence indicates the pronounced effects of physical activity on immune functions, which may largely depend on the type of exercise, intensity, and duration. However, limited information is available regarding the effects of low-impact exercises, especially on the level of adaptive immune system. Our study aimed to investigate and compare the changes in a broad spectrum of lymphocyte subtypes after 14 weeks of aerobic-type total-body-shaping workouts (TBSW) and Pilates workouts (PW) among healthy individuals. We determined the percentages of peripheral natural killer cells and different T and B lymphocyte subtypes with flow cytometry. At the end of the exercise program, significant changes in naïve and memory lymphocyte ratios were observed in TBSW group. Percentages of naïve cytotoxic T (Tc) cells elevated, frequencies of memory Tc and T-helper cell subsets decreased, and distribution of naïve and memory B cells rearranged. Proportions of activated T cells also showed significant changes. Nonetheless, percentages of anti-inflammatory interleukin (IL)-10-producing regulatory type 1 cells and immunosuppressive CD4+CD127lo/−CD25bright T regulative cells decreased not only after TBSW but also after PW. Although weekly performed aerobic workouts may have a more pronounced impact on the adaptive immune system than low-impact exercises, both still affect immune regulation in healthy individuals.

Chronic lymphocytic leukaemia (CLL) is characterised by malignant mature-like B cells. Supportive to CLL cell survival is chronic B-cell receptor (BCR) signalling; however, emerging evidence demonstrates CLL cells proliferate in response to T-helper (Th) cells in a CD40L-dependent manner. We showed provision of Th stimulation via CD40L upregulated CD45 phosphatase activity and BCR signalling in non-malignant B cells. Consequently, we hypothesised Th cell upregulation of CLL cell CD45 activity may be an important regulator of CLL BCR signalling and proliferation. Using patient-derived CLL cells in a culture system with activated autologous Th cells, results revealed increases in both Th and CLL cell CD45 activity, which correlated with enhanced downstream antigen receptor signalling and proliferation. Concomitantly increased was the surface expression of Galectin-1, a CD45 ligand, and CD43, a CLL immunophenotypic marker. Galectin-1/CD43 double expression defined a proliferative CLL cell population with enhanced CD45 activity. Targeting either Galectin-1 or CD43 using silencing, pharmacology, or monoclonal antibody strategies dampened CD45 activity and CLL cell proliferation. These results highlight a mechanism where activated Th cells drive CLL cell BCR signalling and proliferation via Galectin-1 and CD43-mediated regulation of CD45 activity, identifying modulation of CD45 phosphatase activity as a potential therapeutic target in CLL.

Age-related changes of the immune system lead to an increased morbidity and mortality due to enhanced vulnerability to infectious diseases and malignancies. Recent studies revealed the important effects of physical activity on immune functions, which may largely depend on the type of exercise, its intensity and duration. However, limited information is available regarding the immunological effects of sport activities in older ages. The aim of our study was to examine the changes in a wide spectrum of lymphocyte subtypes after regular workout among healthy elderly individuals. We enrolled 29 elderly women with sedentary lifestyle (mean age: 67.03 ± 3.74 years) to take part in a 6-week long functional conditioning gymnastic exercise program. The percentages of peripheral natural killer (NK), NKT cells, T and B lymphocyte subtypes (early-/late-activated T, naïve and memory T, cytotoxic T (Tc), T-helper (Th)1, Th2, Th17, T regulatory type 1 (Tr1), CD4+CD127lo/-CD25bright Treg, as well as naïve and memory B cells) were determined by flow cytometry. Evaluation of the changes in functional capability of Treg cells was based on in vitro functional assays. At the end of exercise program, in parallel with improvements in body composition and physical performance, significant changes in naïve and memory lymphocyte ratios were observed. Importantly, levels of naïve Tc cells elevated, ratios of effector memory Tc cells decreased and distribution of memory B cells rearranged as well. Additionally, proportions of late-activated HLA-DR+ T cells increased, while percentages of anti-inflammatory interleukin (IL)-10 producing Tr1 cells, as well as immunosuppressive CD4+CD127lo/-CD25bright Treg cells decreased following the exercise workout. Changes observed after the regular exercise program indicate an improvement in the age-related redistribution of certain naïve and memory cell proportions and a retuned immune regulation in older ages.

Since B-cell hyperactivity and pathologic antibody response are key features in the immunopathogenesis of primary Sjögren's syndrome (pSS), the role of follicular T helper (TFH) cells as efficient helpers in the survival and differentiation of B cells has emerged. Our aim was to investigate whether a change in the balance of circulating (c)TFH subsets and follicular regulatory T (TFR) cells could affect the distribution of B cells in pSS. Peripheral blood of 38 pSS patients and 27 healthy controls was assessed for the frequencies of cTFH cell subsets, TFR cells, and certain B cell subpopulations by multicolor flow cytometry. Serological parameters, including anti-SSA, anti-SSB autoantibodies, immunoglobulin, and immune complex titers were determined as part of the routine diagnostic evaluation. Patients with pSS showed a significant increase in activated cTFH cell proportions, which was associated with serological results. Frequencies of cTFH subsets were unchanged in pSS patients compared to healthy controls. The percentages and number of cTFR cells exhibited a significant increase in autoantibody positive patients compared to patients with seronegative pSS. The proportions of transitional and naïve B cells were significantly increased, whereas subsets of memory B cells were significantly decreased and correlated with autoantibody production. Functional analysis revealed that the simultaneous blockade of cTFH and B cell interaction with anti-IL-21 and anti-CD40 antibodies decreased the production of IgM and IgG. Imbalance in TFH subsets and TFR cells indicates an ongoing over-activated humoral immune response, which contributes to the characteristic serological manifestations and the pathogenesis of pSS.

Summary Humoral immunity relies on the efficient differentiation of memory B cells (MBCs) into antibody-secreting cells (ASCs). T helper (Th) signals upregulate B cell receptor (BCR) signaling by potentiating Src family kinases through increasing CD45 phosphatase activity (CD45 PA). In this study, we show that high CD45 PA in MBCs enhances BCR signaling and is essential for their effective ASC differentiation. Mechanistically, Th signals upregulate CD45 PA through intensifying the surface binding of a CD45 ligand, Galectin-1. CD45 PA works as a sensor of T cell help and defines high-affinity germinal center (GC) plasma cell (PC) precursors characterized by IRF4 expression in vivo. Increasing T cell help in vitro results in an incremental CD45 PA increase and enhances ASC differentiation by facilitating effective induction of the transcription factors IRF4 and BLIMP1. This study connects Th signals with BCR signaling through Galectin-1-dependent regulation of CD45 PA and provides a mechanism for efficient ASC differentiation of MBCs.

Oncorheumatology is the meeting point of tumour formation and rheumatic diseases. Multiple interactions exist between these two medical specialties. One major field is the topic of malignancies associated with rheumatic diseases, while the other topic covers the development of musculoskeletal disease in cancer patients. In the first group, secondary malignancies associated with rheumatic diseases, role of tumour-associated antigens in rheumatology, the possible carcinogenicity of conventional and targeted antirheumatic drugs and physical therapy of rheumatic patients with recent or current cancer will be discussed. The second large topic includes paraneoplastic syndromes, autoimmune-rheumatic side effects of oncotherapies (chemotherapy and immunotherapy), effects of hormone-deprivation therapies on bone and primary and secondary malignancies of the musculoskeletal system. Orv Hetil. 2020; 161(28): 1151-1165.

Absztrakt: Az onkoreumatológia a daganatképződés és a reumatológiai kórképek kapcsolatát jelenti. Számos összefüggés van a két orvosi szakterület között. Ezek egy része a reumatológiai kórképben szenvedő betegben jelentkező daganatokat, a másik fele pedig a daganatos betegen fellépő mozgásszervi jelenségeket foglalja magában. Az előbbi csoport keretében a reumatológiai betegségekben jelentkező szekunder tumorokat, a tumorasszociált antigének reumatológiai szerepét, a mozgásszervi betegségek kezelésére használt hagyományos és célzott terápiák esetleges onkogenitását és a korábban vagy jelenleg daganatos, mozgásszervi betegek fizioterápiáját tárgyaljuk. A másik nagy csoport magában foglalja a paraneoplasiás szindrómákat, az onkológiai kezelések (kemoterápia és immunterápia) lehetséges autoimmun-reumatológiai mellékhatásait, a hormondeprivatiós kezelés csonthatásait és a mozgásszervrendszer primer és szekunder daganatait. Orv Hetil. 2020; 161(28): 1151–1165.

Oncorheumatology: relationship between malignancies and musculoskeletal diseases: Oncorheumatology is the meeting point of tumor formation and rheumatic musculoskeletal diseases (RMD). Multiple interactions exist between these two medical specialties. One major field is the topic of malignancies associated with rheumatic diseases, while the other topic covers the development of musculoskeletal disease in cancer patients. Within the first group, secondary malignancies may be associated with rheumatic diseases. Mostly sustained inflammation is responsible for transition into cancer. Tumor-associated antigens (TAA) with adhesive properties are present on tumor cells. These molecules may also be expressed by inflammatory leukocytes and soluble TAA levels may be elevated in RMDs. There has been continuous debate with respect to the possible carcinogenicity of conventional and targeted antirheumatic drugs. Very recent data from registries suggest that neither biologics, nor JAK inhibitors increase cancer risk in arthritis patients. The issue of physiotherapy in rheumatic patients with recent or current cancer has also been controversial. Some modalities, primarily exercise, may be safely applied to patients with RMD and cancer. The second large topic includes paraneoplastic syndromes. Musculoskeletal paraneoplasias are triggered by tumor-derived mediators. These syndromes are sometimes slightly different from the classical RMDs. Various chemotherapies may also be associated with autoimmune side effects. Recently, these immune-related complications have also been observed in cancer patients treated with immune-checkpoint inhibitors. Sex hormone-deprivation therapies, such as aromatase inhibitors and anti-androgens are widely used for the treatment of breast and prostate cancer, respectively. These compounds may induce bone loss and lead to osteoporosis. Finally, primary and secondary malignancies of the musculoskeletal system may also interest rheumatologists. In this review, the clinical, practical aspects of these eight pillars of oncorheumatology will be discussed.

AIM:To evaluate detailed anterior segment parameters of patients with idiopathic inflammatory myopathies（IIM）,including polymyositis（PM）,and dermatomyositis（DM）,and to clarify the associations between these data and clinical variables of IIM.METHODS:Totally 57 PM,41 DM patients and 62 controls were enrolled in this cross-sectional,observational,case-control study.All study participants underwent Pentacam evaluation.Laboratory investigations consisted of different antibody assays,while extramuscular clinical assessments included Raynaud’s phenomenon,dysphagia,interstitial lung disease,arthritis/arthralgia,and weight loss.Objective signs and subjective symptoms of dry eye disease（DED） were also evaluated.RESULTS:All pachymetric parameters [center,apex,thinnest and maximal keratometry(K max )] and corneal volume（CV） of both sides of PM patients proved to be significantly lower.Some pachymetric data were also noticed as significantly decreased compared to those of controls.Several significant differences were traced between anterior segment values and extramuscular manifestations of myositis,largely in case of arthritis/arthralgia and weight loss,whereas associations between anterior segment parameters and antibodies were weak.Objective clinical tests of DED were also significantly decreased in IIM patients.CONCLUSION:The results suggest that all IIM patients have thinner corneas compared with those of controls,and decreased corneal parameters are significantly associated with the occurrence of some extramuscular manifestations.In addition,IIM patients tend to develop objective signs of DED.

Aim To evaluate tear film parameters and relationship of objective clinical signs and subjective symptoms of dry eye disease (DED) in inflammatory bowel disease (IBD) subgroups. Methods 39 patients with Crohn's disease (CD), 26 patients with ulcerative colitis (UC), and 39 control persons with no ocular symptoms or surface disorders were included in this prospective, case-control, and cross-sectional study. The ocular surface disease index (OSDI) questionnaire was applied to evaluate dry eye symptoms, and objective tests of DED were performed on both eyes of each subject. Results The average of OSDI scores was 30.59 (±16.68) in CD patients, 24.67 (±23.48) in UC patients, and 11.19 (±5.8) in controls. Except for tear film breakup time (tBUT) and Schirmer-I values other objective parameters were better in UC patients, than in CD patients. CD patients rather than UC patients tend to develop DED. This was associated with immunosuppressant and TNF-α inhibitor use. Conclusions Clinicians must be aware of the spectrum of DED involvement in IBD and suggest using artificial tears in order to decrease severity of ocular complications.

Purpose Our aim was to summarize key aspects of the pathomechanism and the ocular involvements of rheumatic and systemic autoimmune diseases. Methods Apart from a paper in French (Morax V, Ann Oculist 109:368–370, 1893), all papers referred to in this article were published in English. All the materials were peer-reviewed full-text papers, letters, reviews, or book chapters obtained through a literature search of the PubMed database using the keywords ocular manifestations; pathogenesis; systemic inflammatory rheumatic diseases; rheumatoid arthritis; osteoarthritis; fibromyalgia; systemic lupus erythematosus; seronegative spondyloarthritis; ankylosing spondylitis; reactive arthritis; enteropathic arthritis; psoriatic arthritis; systemic sclerosis; polymyalgia rheumatica and covering all years available. Some statements articulated in this paper reflect the clinical experience of the authors in their tertiary-referral center. Results Ophthalmic disorders are categorized by anatomical subgroups in all rheumatic diseases. The most common ocular manifestations are diverse types of inflammations of different tissues and dry eye disease (DED). Conclusion The eye could be a responsive marker for the onset or aggravation of an immune reactivation in many rheumatic diseases, furthermore, ocular findings can antedate the diagnosis of the underlying rheumatic disease. By recognizing ocular manifestations of systemic rheumatic diseases it might be possible to avoid or at least delay many long term sequelae.