The Everted Acetabular Labrum: Patho-anatomy, Magnetic Resonance Imaging and Arthroscopic Findings of a Native Variant.

PURPOSE: The purpose of this study was to introduce a native labral variant, the everted acetabular labrum, and to describe the patho-anatomy, magnetic resonance imaging and magnetic resonance arthrogram (MRI/MRA) characteristics and the arthroscopic findings in this condition. METHODS: All primary hip arthroscopy procedures performed by the senior author between June 2013 and January 2020 were reviewed retrospectively. An everted acetabular labrum was identified as a segment of labrum that lacked apposition to the femoral head with the hip off traction. All everted labra were treated with labral advancement and repair with or without augmentation or reconstruction. The labrum-to-femoral head distance was measured in 3T MRI/MRA at the 1-2 o'clock position. A random selection of 38 hips without an everted labrum served as controls to compare radiographic parameters. RESULTS: A total of 68 hips were identified as having an everted labrum during the study period (mean age, 29.1 years), and 55 hips had advanced imaging available for review. MRI/MRA scans revealed the everted labrum to have a triangular shape in 17 hips (31%) and a blunted/round shape in 38 hips (69%), which differed significantly from controls (triangular 25/38 [66%], blunted 13/38 [34%], P < 0.001). The average labrum-to-femoral head distance was 1.4 mm for everted labra versus 0.0 mm for controls (P < 0.0001) and the mean labral lengths and widths were significantly shorter than those of controls (both P < 0.01). Of the hips, 8 underwent labral reconstruction or augmentation, and 61 underwent labral advancement/repair. CONCLUSION: The everted acetabular labrum is a native variant that is identifiable during hip arthroscopy by assessing the labral seal off traction. Preoperative MRI/MRA findings can be highly predictive of an everted labrum. Surgical treatment includes labral advancement and repair or reconstruction to restore contact between the labrum and the femoral head. LEVEL OF EVIDENCE: III, retrospective comparative study.

Determining glenoid component version after total shoulder arthroplasty.

BACKGROUND: Glenoid component loosening after total shoulder arthroplasty (TSA) may occur if retroversion is not corrected to <10°. However, accurately measuring postoperative glenoid component version has been difficult without postoperative computed tomography (CT), adding cost and radiation exposure outside of the standard radiographic follow-up. We present a new method to assess glenoid component version after TSA using only routine preoperative CT and postoperative radiographs (x-rays). METHODS: Preoperative glenoid version was measured using established methods with an axillary x-ray, 2-dimensional CT, and Glenosys software (Imascap, Plouzané, France). Postoperative glenoid component version and inclination were measured for 61 TSA patients using Mimics software (Materialise, Leuven, Belgium) with preoperative CT and postoperative x-rays. Four patients also had postoperative CTs. Glenoid implantation and imaging were performed on 14 cadavers, allowing validation of results against the gold standard postoperative CT glenoid retroversion measurement. RESULTS: Compared with the gold standard, retroversion and inclination measurement error was 2° ± 1° and 2° ± 1°, respectively. Average postoperative version correction was 6° ± 7°, with 35 of 61 patients (57%) corrected to <10° of retroversion. Correlation between preoperative version measurement methods was good to very good, except on the axillary x-ray. Patients not corrected to <10° of retroversion had significantly higher preoperative retroversion (14° ± 6°) than those corrected to <10° (6° ± 7°; P < .00001). CONCLUSIONS: Glenoid component retroversion after TSA can be accurately measured with a method using only routine preoperative CT and postoperative x-rays, validated to within 1.9° of the gold standard postoperative CT measurement. Future studies using this method may correlate glenoid retroversion correction with glenoid component longevity to help optimize shoulder arthroplasty outcomes.

Trends in Management and Complications of Anterior Cruciate Ligament Injuries in Pediatric Patients: A Survey of the PRiSM Society.

BACKGROUND: Anterior cruciate ligament (ACL) injuries have been recognized and treated with increasing frequency in children and adolescents. ACL reconstruction (ACLR) in skeletally immature patients has unique considerations and there is a large practice variation in the management of these injuries. The purpose of this study was to survey the members of the Pediatric Research in Sports Medicine (PRiSM) Society regarding their experience with the management and complications of pediatric ACL injuries. METHODS: A 15-question survey was distributed to 71 orthopaedic members of the Pediatric Research in Sports Medicine study group. RESULTS: Regarding treatment of an 8-year-old child with a complete ACL tear, 53% of respondents recommended iliotibial band reconstruction, 33% recommended all-epiphyseal reconstruction, and only 3% would treat nonoperatively in a brace. In adolescent patients with 2 years of growth remaining, 47% of respondents recommended a physeal "respecting" technique, 31% recommended a physeal-sparing technique, and 19% would perform an adult-style ACLR. There were 29 new cases of growth arrest reported. CONCLUSIONS: This study demonstrates that there have been major changes in the trends in pediatric ACLR over the past 15 years, and the most treatment variability is found among adolescent patients with about 2 years of growth remaining. The study also demonstrates that while the overall incidence of growth disturbance after ACLR remains low, new cases of growth disturbance continue to be identified. LEVEL OF EVIDENCE: Level V-survey of expert opinion and experience.

The effect of environmental temperature on reptilian peripheral blood B cell functions.

Recent studies have identified phagocytic B cells in a variety of species, yet little is understood about their function and how it is influenced by natural environmental variation, such as temperature. Phagocytic B-cells are present in red-eared slider turtles, Trachemys scripta, and the wide range of temperatures experienced by these ectotherms may have an effect on immunity, including B cell antibody secretion and phagocytosis. We examined the impact of environmental temperature on B cell function in vitro using phagocytic and ELISpot assays conducted at biologically relevant temperatures. We found a significant effect of temperature on antibody secretion, with maximal antibody secretion occurring at intermediate temperatures (estimated maximum of 28.8°C). There was no effect of temperature on phagocytosis. We also noted a difference in the efficiency of phagocytosis in this assay between B cells and non-B cells. Interestingly, in our in vitro assay, phagocytic B cells engulfed more foreign fluorescent beads per cell than phagocytes lacking surface immunoglobulin. This work sheds light on our understanding of phagocytic B cells and the importance of environmental temperature on the behavior of reptilian immune cells, which may have relevance for organismal fitness.

Genetic and environmental variation in condition, cutaneous immunity, and haematocrit in house wrens.

BACKGROUND: Life-history studies of wild bird populations often focus on the relationship between an individual's condition and its capacity to mount an immune response, as measured by a commonly-employed assay of cutaneous immunity, the PHA skin test. In addition, haematocrit, the packed cell volume in relation to total blood volume, is often measured as an indicator of physiological performance. A multi-year study of a wild population of house wrens has recently revealed that those exhibiting the highest condition and strongest PHA responses as nestlings are most likely to be recruited to the breeding population and to breed through two years of age; in contrast, intermediate haematocrit values result in the highest recruitment to the population. Selection theory would predict, therefore, that most of the underlying genetic variation in these traits should be exhausted resulting in low heritability, although such traits may also exhibit low heritability because of increased residual variance. Here, we examine the genetic and environmental variation in condition, cutaneous immunity, and haematocrit using an animal model based on a pedigree of approximately 2,800 house wrens. RESULTS: Environmental effects played a paramount role in shaping the expression of the fitness-related traits measured in this wild population, but two of them, condition and haematocrit, retained significant heritable variation. Condition was also positively correlated with both the PHA response and haematocrit, but in the absence of any significant genetic correlations, it appears that this covariance arises through parallel effects of the environment acting on this suite of traits. CONCLUSIONS: The maintenance of genetic variation in different measures of condition appears to be a pervasive feature of wild bird populations, in contradiction of conventional selection theory. A major challenge in future studies will be to explain how such variation persists in the face of the directional selection acting on condition in house wrens and other species.

Neonatal body condition, immune responsiveness, and hematocrit predict longevity in a wild bird population.

Measures of body condition, immune function, and hematological health are widely used in ecological studies of vertebrate populations, predicated on the assumption that these traits are linked to fitness. However, compelling evidence that these traits actually predict long-term survival and reproductive success among individuals in the wild is lacking. Here, we show that body condition (i.e., size-adjusted body mass) and cutaneous immune responsiveness to phytohaemagglutinin (PHA) injection among neonates positively predict recruitment and subsequent longevity in a wild, migratory population of house wrens (Troglodytes aedon). However, neonates with intermediate hematocrit had the highest recruitment and longevity. Neonates with the highest PHA responsiveness and intermediate hematocrit prior to independence eventually produced the most offspring during their lifetime breeding on the study site. Importantly, the effects of PHA responsiveness and hematocrit were revealed while controlling for variation in body condition, sex, and environmental variation. Thus, our data demonstrate that body condition, cutaneous immune responsiveness, and hematocrit as a neonate are associated with individual fitness. Although hematocrit's effect is more complex than traditionally thought, our results suggest a previously underappreciated role for this trait in influencing survival in the wild.

Superior labrum anterior-to-posterior repair incidence: a longitudinal investigation of community and academic databases.

BACKGROUND: Superior labrum anterior-to-posterior (SLAP) lesion repair is controversial regarding indications and potential complications. METHODS: Databases were used to determine the SLAP repair incidence compared with all orthopaedic procedures over a period of 10 years. In part A, the New York Statewide Planning and Research Cooperative System ambulatory surgery database was investigated from 2002 to 2009. In part B, the California Office of Statewide Health Planning and Development ambulatory surgery database was investigated from 2005 to 2009. In part C, the American Board of Orthopaedic Surgery (ABOS) database was investigated from 2003 to 2010. RESULTS: In part A, from 2002 to 2009, there was a 238% increase in SLAP repair volume compared with a 125% increase in all orthopaedic procedures. In part B, from 2005 to 2009, there was a 20.17% increase in SLAP repair volume compared with a decrease of 13.64% in all orthopaedic procedures. In part C, among candidates performing at least 1 SLAP repair, there was no statistically significant difference in likelihood of performing a SLAP repair (95% confidence interval, 0.973-1.003) in 2010 as compared with 2003 (P > .10). CONCLUSIONS: There has been a significant increase in the incidence of SLAP repairs in the past 10 years in statewide databases. This pattern was not seen in the ABOS database, in which the annual volume of SLAP repairs remained stable over the same period. This suggests that SLAP lesions have been over-treated with surgical repair but that part II ABOS candidates are becoming more aware of the need to narrow indications. LEVEL OF EVIDENCE: Epidemiology study, database analysis.

The Everted Acetabular Labrum: Outcomes of Surgical Management.

BACKGROUND: An everted acetabular labrum (EL) is a pathologic variant in which the labrum is flipped to the capsular side of the acetabular rim. An iatrogenic EL is a known complication of a poorly executed labral repair, and a recent study described the native acetabular EL. PURPOSE: To analyze surgical outcomes after advancement or reconstruction of an EL in a native hip. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: This was a multicenter retrospective review of prospectively collected data on primary hip arthroscopic surgeries performed between 2013 and 2023. An EL was identified arthroscopically as a labrum-femoral head gap while off traction in the native hip. All patients with EL who were analyzed in this study underwent arthroscopic labral repair and advancement or labral augmentation or reconstruction. Patients with hip dysplasia also underwent periacetabular osteotomy with or without a derotational femoral osteotomy. Patient-reported outcomes (PROs) were assessed using the 12-item International Hip Outcome Tool (iHOT-12) and the Nonarthritic Hip Score. PROs were obtained preoperatively and up to 24 months after surgery. PROs were compared with those of a case-matched control cohort in a 1:2 ratio. Only patients with PROs available at ≥1 year postoperatively were included in the outcome analysis. RESULTS: A total of 111 patients (129 hips) with EL during the study period were identified, with PROs available in 96 hips. The mean age of patients with EL was 30.5 years, and women made up 87% of the cohort. Of the 129 hips with an EL, an isolated diagnosis of an EL was present in 11.6% of hips. Deficient acetabular coverage (lateral center-edge angle <25°) was seen in 40.6% of EL hips. No difference was seen in iHOT-12 scores between EL and control groups at 12- or 24-month follow-up (P = .18 and .94, respectively). Patients with EL reported a significant improvement of PROs at latest follow-up (P < .001 for iHOT-12 and Nonarthritic Hip Score). CONCLUSION: Surgical management of a native EL with restoration of the labral seal on the femoral head and correction of concomitant pathologies resulted in significant clinical improvement, with postoperative outcome scores comparable to those of patients without an EL. These findings provide evidence supporting surgical intervention for a native EL.

Humoral immune responses are maintained with age in a long-lived ectotherm, the red-eared slider turtle.

Aging is typically associated with a decrease in immune function. However, aging does not affect each branch of the immune system equally. Because of these varying effects of age on immune responses, aging could affect taxa differently based on how the particular taxon employs its resources towards different components of immune defense. An example of this is found in the humoral immune system. Specific responses tend to decrease with age while non-specific, natural antibody responses increase with age. Compared with mammals, reptiles of all ages have a slower and less robust humoral immune system. Therefore, they may invest more in non-specific responses and thus avoid the negative consequences of age on the immune system. We examined how the humoral immune system of reptiles is affected by aging and investigated the roles of non-specific, natural antibody responses and specific responses by examining several characteristics of antibodies against lipopolysaccharide (LPS) in the red-eared slider turtle. We found very little evidence of immunosenescence in the humoral immune system of the red-eared slider turtle, Trachemys scripta, which supports the idea that non-specific, natural antibody responses are an important line of defense in reptiles. Overall, this demonstrates that a taxon's immune strategy can influence how the immune system is affected by age.

No evidence that estrogens affect the development of the immune system in the red-eared slider turtle, Trachemys scripta.

Exposure to maternally derived substances during development can affect offspring phenotype. In ovo exposure to maternally derived steroids has been shown to influence traits such as growth and behavior in the offspring. The development of the immune system also can be altered by exposure to both androgens and glucocorticoids in a variety of species, but much less is known about the potential for estrogens to influence the development of this system. We examined the effect of estradiol on the development of both innate and adaptive immune components in the red-eared slider turtle (Trachemys scripta). A bacterial killing assay was used to assess innate immunity, a delayed-type hypersensitivity test for cellular immunity, and total immunoglobulin levels to measure the humoral immune response. We found no effect of in ovo estradiol treatment on any of our immune measures despite using doses that are known to influence other phenotypic parameters during development and varying the timing of dosing across development. Our results suggest that maternally derived estradiol does not affect the development of the immune system in T. scripta.

ACL injury and surgical treatment options.

The anterior cruciate ligament (ACL) has been the focus of a substantial amount of research. Thousands of studies have evaluated the structure and function of the intact ACL, as well as the best reconstruction techniques. Despite the amount of literature, many controversies remain regarding the ACL and its surgical reconstruction. This article reviews the anatomy and function of the native ACL, the nature of injury, and aspects of ACL reconstruction, including surgical approach, tunnel positioning, graft choice, and graft fixation.

Variation in the seasonal patterns of innate and adaptive immunity in the red-eared slider (Trachemys scripta).

The primary function of the immune system is to protect the organism from invading pathogens. In vertebrates, this has resulted in a multifaceted system comprised of both innate and adaptive components. The immune system of all jawed vertebrates is complex, but unlike the endothermic vertebrates, relatively little is known about the functioning of the ectothermic vertebrate immune system, especially the reptilian system. Because turtles are long-lived ectotherms, factors such as temperature and age may affect their immune response, but comprehensive studies are lacking. We investigated variation in immune responses of adult male and female red-eared sliders (Trachemys scripta) across the entire active season. We characterized seasonal variation in innate, cell-mediated and humoral components via bactericidal capacity of plasma, delayed-type hypersensitivity and total immunoglobulin levels, respectively. Results indicate that all immune measures varied significantly across the active season, but each measure had a different pattern of variation. Interestingly, temperature alone does not explain the observed seasonal variation. Immune measures did not vary between males and females, but immunoglobulin levels did vary with age. This study demonstrates the highly dynamic nature of the reptilian immune system, and provides information on how biotic and abiotic factors influence the immune system of a long-lived ectotherm.

Phagocytic B cells in a reptile.

Evidence for a developmental relationship between B cells and macrophages has led to the hypothesis that B cells evolved from a phagocytic predecessor. The recent identification of phagocytic IgM+ cells in fishes and amphibians supports this hypothesis, but raises the question of when, evolutionarily, was phagocytic capacity lost in B cells? To address this, leucocytes were isolated from red-eared sliders, Trachemys scripta, incubated with fluorescent beads and analysed using flow cytometry and confocal microscopy. Results indicate that red-eared slider B cells are able to ingest foreign particles and suggest that ectothermic vertebrates may use phagocytic B cells as part of a robust innate immune response.

Osteochondral Fracture Fixation With Fragment Preserving Suture Technique.

Osteochondral fractures are relatively uncommon injuries that typically present after an acute or subacute traumatic injury. Osteochondral fracture fixation is traditionally performed in the acute setting with internal fixation procedures using pins or compression screws through the fragment. Outcomes have generally been good, but cartilage thinning, subchondral remodeling, and tissue reactions can occur after internal fixation through the fragment. This article describes osteochondral fracture fragment fixation with a fragment-preserving technique that does not violate the articular cartilage of the fragment. This technique minimizes risk to articular cartilage that has already sustained injury and also provides superior fixation.

Citalopram enhances B cell numbers in a murine model of morphine-induced immunosuppression.

Patients with chronic pain are often challenged with depression stemming from the long-term psychophysiological effects of their condition. Consequently, patients with chronic pain are often treated with morphine, which can induce immunosuppression, along with an antidepressant. The antidepressant citalopram (CTP; Sigma-Aldrich Chemical, St. Louis, MO, U.S.A.) is a serotonin reuptake inhibitor that is reported to have immunomodulatory effects. Thus, we investigated whether CTP administration impacted immunity in morphine-treated animals. Adult mice were pretreated for 7 days with either saline or CTP (10 or 30 mg/kg intraperitoneal injections twice daily), followed by subcutaneous implantation of a 25 mg morphine pellet for 48 hours. Spleen, thymus, and lymph nodes were harvested to analyze total cell numbers, relative lymphocyte populations, and lymphocyte function. In this study, CTP had no effect on either total cell counts or lymphocyte populations in the thymus. However, in the spleen, total splenocyte numbers in all CTP-treated animals displayed an increasing trend over saline-treated animals. Interestingly, although more cells were found in the spleen, distribution of splenic lymphocyte populations did not differ between treatments. Despite no increase in total cell number, a high dose of CTP (30 mg/kg) resulted in a significantly higher B cell population in the lymph nodes, while T cell and NK cell numbers were not different. CTP did not significantly reverse morphine-induced weight loss or splenic B cell antibody secretion in vitro. Additionally, CTP treatment demonstrated a slight but not significant increase in both splenic B and T cell mitogen-induced proliferation in vitro. In summary, CTP may have a specific potential in the attenuation of morphine's immunosuppressive effect by enhancing splenocyte numbers and lymph node B cell populations.

Trochleoplasty, Medial Patellofemoral Ligament Reconstruction, and Open Lateral Lengthening for Patellar Instability in the Setting of High-Grade Trochlear Dysplasia.

Trochlear dysplasia is the most commonly encountered pathoanatomy in patients who present with patellar instability. Outcomes of trochleoplasty procedures have shown low rates of recurrent instability and high patient-reported outcome scores. This article describes a "thin-flap" groove-deepening trochleoplasty combined with medial patellofemoral ligament reconstruction with a gracilis allograft and lateral retinacular lengthening to treat recurrent patellar instability due to high-grade trochlear dysplasia. This technique can obviate tibial tubercle osteotomy by normalizing the position of the trochlear groove and, subsequently, decreasing the tibial tubercle-to-trochlear groove distance.

Intestinal B cells in the red-eared slider turtle, Trachemys scripta: Anatomical distribution and implications for ecological interactions with pathogenic microbes.

Disease is a significant threat in the global decline of reptile species. Many aquatic reptiles live in habitats with high levels of opportunistic microbial pathogens, yet little is known about their immune system. Gut-associated lymphoid tissue is vital for protection against ingested pathogens and maintenance of normal gut microbiota. In mammals, gut mucosal immunity is well-characterized and mucosal surfaces are coated in protective antibodies. However, reptiles lack lymph nodes and Peyer's patches, which are the major sites of mammalian B cell responses. The presence or distribution of mucosal B cells in reptiles is unknown. In this study, we first set out to determine if B cells could be detected in intestinal tissues of red-eared slider turtles, Trachemys scripta. Using whole-mount immunochemistry and a primary antibody to turtle antibody light chains, we identified widely distributed B cell aggregates within the small intestine of hatchling turtles. These aggregates appeared similar to isolated lymphoid follicles (ILFs) in mammals and the frequency was much higher in distal intestinal sections than in proximal sections. To determine if these structures were inducible in the presence of microbes, we introduced an enteric Salmonella species through oral gavage. Analysis of intestinal tissues revealed that hatchlings exposed to Salmonella exhibited significantly more of these aggregates when compared with those that did not receive bacteria. These studies provide the first evidence for B cell-containing ILF-like structures in reptiles and provide novel information about gut immunity in nonmammalian vertebrates that could have important implications for ecological interactions with pathogens.

Female house wrens (Troglodytes aedon) increase the size, but not immunocompetence, of their offspring through extra-pair mating.

House wrens are typically socially monogamous, but frequently engage in extra-pair matings leading to multisired broods. Because females do not appear to acquire direct material benefits from their extra-pair mates, we tested the hypothesis that female house wrens derive indirect genetic benefits, such as enhanced immunocompetence (cutaneous immune activity, humoral immunity, and plasma bactericidal activity) and condition (size and haematoserological traits) for their offspring, by mating polyandrously. We predicted that extra-pair young (EPY) should show greater immune responsiveness and better body condition than their within-pair maternal half-siblings (WPY). Contrary to our prediction, WPY had higher cutaneous immune activity than their EPY brood-mates in two of three years, and EPY and WPY did not differ in measures of innate and humoral immunity. WPY also had higher albumin to gamma-globulin ratios than EPY; however, they were not in better condition based on other measures. EPY had consistently longer tarsi (a measure of long-bone size) than their WPY half-siblings, suggesting that females engage in extra-pair copulations with larger males. The benefits of large structural size in the study population is unknown, but based on evidence from other passerines, we suggest that structural size may be an important fitness-related trait in house wrens. We conclude that our results are not consistent with the hypothesis that females gain immune-related benefits for their offspring by engaging in extra-pair matings. Further study of the fitness consequences of differences in tarsus length is needed to determine whether females acquire size-related benefits for their offspring from extra-pair mates.

Aged B lymphocytes retain their ability to express surface markers but are dysfunctional in their proliferative capability during early activation events.

BACKGROUND: Ageing is associated with dysfunction in the humoral response leading to decreased protection against infectious diseases. Defects in T cell function due to age have been well characterized but it is unclear if dysfunctions in antibody responses are due to deficiencies in a helper environment or intrinsic B cell defects. Previous studies from our laboratory have shown that aged B lymphocytes are able to differentiate into high affinity antibody-secreting cells at a frequency similar to their young counterparts. However, expansion of B cells in vivo was reduced in aged animals when compared to young. METHODS: To further investigate the cause of this reduced expansion, we have now examined early activation events of aged B cells in response to anti-CD40 monoclonal antibody (mAb) and lipopolysaccharide (LPS) stimulation in vitro. To do this spleen cells were harvested from young, middle-aged and aged quasi-monoclonal (QM) mice and cultured in complete RPMI for 24 and 48 hours. Cultures contained either LPS or anti-CD40 mAb and murine IL-4. Cells were collected and analyzed using flow cytometry. To examine the proliferative capacity of aged B cells spleen cells were collected as before and cultured in 96 well microtiter plates with either LPS or anti-CD40 mAb and murine IL-4 for 24 hours. Tritiated thymidine ([3H]-Tdr) was added to each well and incubated for another 24 hours after which cells were collected and analyzed using a scintillation counter. RESULTS: Resting aged B cells exhibited similar levels of CD40 expression when compared to young cells and efficiently up-regulated CD86 and CD69 and also down-regulated CD38 upon stimulation. However, aged B cells proliferated less than young B cells and showed a consistent, but not statistically significant, reduction in their ability to form blast cells. CONCLUSION: Aged B cells exhibited a reduced response in some early activation events but produced at least a partial response in all cases. Thus, therapeutic intervention may be possible, despite intrinsically different responses in aged B cells.

Short-circuiting long-lived humoral immunity by the heightened engagement of CD40.

Agonistic alpha CD40 Ab's have been shown to be potent immune adjuvants for both cell- and humoral-mediated immunity. While enhancing short-lived humoral immunity, the administration of a CD40 agonist during thymus-dependent immune responses ablates germinal center formation, prematurely terminates the humoral immune response, blocks the generation of B cell memory, and prevents the generation of long-lived bone marrow plasma cells. Interestingly, some of these effects of heightened CD40 engagement could be mimicked by enhancing the magnitude of antigen-specific T cell help. Taken together, these studies demonstrate that as the magnitude of CD40 signaling intensifies, the fate of antigen-reactive B cells can be dramatically altered. These are the first studies to describe the multifaceted function of CD40 in determining the fate of antigen-reactive B cells and provide novel insights into how CD40 agonists can short-circuit humoral immunity.