key: cord-1012708-qlv1maj4
authors: Rushakoff, Joshua A.; Gragert, Loren; Pando, Marcelo J.; Stewart, Darren; Huang, Edmund; Kim, Irene; Jordan, Stanley; Lindblad, Kelsi; Zhang, Xiaohai; Lalli, Peter; Patel, Jignesh K.; Kobashigawa, Jon A.; Kransdorf, Evan P.
title: HLA Homozygosity and Likelihood of Sensitization in Kidney Transplant Candidates
date: 2022-04-07
journal: Transplant Direct
DOI: 10.1097/txd.0000000000001312
sha: 020781fe58634c6e42254219efa28dfac1f8b984
doc_id: 1012708
cord_uid: qlv1maj4

BACKGROUND. Homozygosity for HLAs has been associated with adverse outcomes after viral infection as well as pregnancy-induced HLA sensitization. We sought to assess the relationship between HLA locus homozygosity and the level of HLA antibody sensitization. METHODS. We measured sensitization using the calculated panel reactive antibody value for a large cohort of 147 461 patients added to the US OPTN/United Network for Organ Sharing kidney transplant waitlist between December 2014 and December 2019. We used multinomial logistic modeling to compare 62 510 sensitized patients to 84 955 unsensitized controls. RESULTS. We found that the number of homozygous HLA loci was strongly associated with the level of sensitization. Within mildly, highly, or extremely sensitized candidates, women displayed a higher relative abundance of HLA homozygosity at multiple HLA loci as compared with men, with attenuation of this effect in Black candidates. In a multivariable logistic model, the number of homozygous HLA loci interacted with female sex but not with other factors associated with sensitization, including recipient ethnicity and a history of prior kidney transplant. CONCLUSIONS. This study shows that HLA homozygosity is an innate genetic factor that affects the likelihood of HLA sensitization. Further research is needed to identify the immunologic mechanisms that underlie this observation.

H LA sensitization remains an important disparity, which limits access to deceased and living donor kidney transplant. 1, 2 Sensitization results from exposure to nonself HLA antigens, most commonly through blood transfusions, 3, 4 pregnancy, 5, 6 and previous organ transplantation. 7, 8 Patient characteristics such as ethnicity 7, 9 are also associated with the level of sensitization, although the biological mechanisms of this remain unclear.

Several aspects of the epidemiology of sensitization remain enigmatic. First, sensitization is a pervasive problem, affecting 25%-40% of candidates for solid organ 10, 11 and stem cell transplants. 12 Next, HLA antibodies can be identified in a small percentage of women and men apheresis donors without a history of pregnancy or transfusion 5, [13] [14] [15] suggesting that additional factors, such as crossreactivity/heterologous immunity, may contribute to sensitization. 16, 17 An individual's HLA genotype is comprised of 2 haplotypes, one inherited from each parent. 18 Compared with other human genes, HLA loci display higher levels of heterozygosity, driven by balancing selection. 19 HLA heterozygosity has been found to be a marker of improved outcomes in a number of viral infections, including human immunodeficiency virus 20 and hepatitis C, 21 as well as in the response to cancer immunotherapy. 22 Conversely, HLA homozygosity has been associated with adverse outcomes in coronavirus disease 2019 23 and an increased risk of lymphoma development. 24 HLA homozygosity has been identified as a risk factor for pregnancy-induced HLA sensitization. 6 In this study, we analyze the relationship between HLA homozygosity and sensitization as measured using the calculated panel reactive antibody (CPRA) value for candidates on the kidney transplant waitlist in the United States. We

Background. Homozygosity for HLAs has been associated with adverse outcomes after viral infection as well as pregnancy-induced HLA sensitization. We sought to assess the relationship between HLA locus homozygosity and the level of HLA antibody sensitization. Methods. We measured sensitization using the calculated panel reactive antibody value for a large cohort of 147 461 patients added to the US OPTN/United Network for Organ Sharing kidney transplant waitlist between December 2014 and December 2019. We used multinomial logistic modeling to compare 62 510 sensitized patients to 84 955 unsensitized controls. Results. We found that the number of homozygous HLA loci was strongly associated with the level of sensitization. Within mildly, highly, or extremely sensitized candidates, women displayed a higher relative abundance of HLA homozygosity at multiple HLA loci as compared with men, with attenuation of this effect in Black candidates. In a multivariable logistic model, the number of homozygous HLA loci interacted with female sex but not with other factors associated with sensitization, including recipient ethnicity and a history of prior kidney transplant.

Conclusions. This study shows that HLA homozygosity is an innate genetic factor that affects the likelihood of HLA sensitization. Further research is needed to identify the immunologic mechanisms that underlie this observation. hypothesized that HLA homozygosity may increase the likelihood of sensitization and sought to evaluate this relationship across patient characteristics including sex and ethnicity.

This study was performed under an approved protocol of the Cedars-Sinai Institutional Review Board (Pro00049901).

We identified 184 828 kidney transplant candidates added to the United Network for Organ Sharing (UNOS) waitlist between December 4, 2014 (the day the Kidney Allocation System took effect) and December 31, 2019 (Figure 1 , SDC, http://links.lww. com/TXD/A415). Because CPRA is only defined for 4 ethnic groups (White, Black, Hispanic/Latinx, and Asian), individuals of other ethnicities (n = 3459) were excluded. There were 33 904 candidates with incomplete HLA typing (of which 0.02% were missing HLA-A, 90.30% HLA-C, 0.02% HLA-B, 0.02% HLA-DR, and 79.20% HLA-DQ) that were also excluded. The final study cohort comprised a nonsensitized group of 84 955 candidates and a sensitized group of 62 510 candidates.

CPRA was calculated for each unique set of HLA-A, -C, -B, -DR, and -DQ unacceptable HLA antigens (UA-HLA), for each candidate. The National Marrow Donor Program (NMDP)-CPRA was used given its greater accuracy for sensitized candidates as compared with UNOS-CPRA. 25 For candidates with >1 CPRA value, the peak CPRA value prior to transplant was utilized. The CPRA calculator was developed in R 26 and previously published. 10 

When present, we converted HLA alleles into UNOS antigen categories using a previously described mapping table. 27 We found that the frequency of homozygosity for HLA split antigens was more prevalent in each successively more sensitized group ( Table 1 , SDC, http://links.lww.com/TXD/A415), suggesting that homozygosity for split antigens is functionally similar to homozygosity for broad antigens. As such, split antigens were mapped to the corresponding broad antigen using a mapping table (Table 2 , SDC, http://links.lww.com/TXD/ A415). HLA homozygosity was determined based on the broad HLA antigen assignments for the HLA-A, -C, -B, -DR, and -DQ loci and candidates were designated as homozygotes if both antigens at a locus were identical. To assess if HLA antigen frequencies matched a reference population dataset, homozygosity for each antigen was calculated for each ethnic group in the study cohort and compared with the NMDP registry ( 

The relationship between the number of homozygous HLA loci and CPRA for each candidate was nonlinear (Figure 2 , SDC, http://links.lww.com/TXD/A415). Thus, multinomial logistic modeling was used for analysis, with sensitization stratified into 4 groups based on the peak CPRA during listing/ prior to transplant: (1) nonsensitized (no UA-HLA or CPRA = 0); (2) mildly sensitized (CPRA 1-69); (3) highly sensitized (CPRA 70-94); and (4) extremely sensitized (CPRA 95-100). CPRA thresholds for each sensitization group were based on assigning the 17 CPRA categories for candidates in the kidney allocation system into 3 groups of successively higher levels of sensitization composed of 6, 5, and 6 categories, respectively.

Single and multivariable multinomial modeling was performed to determine the relationship between the number of homozygous HLA loci (assessed on an ordinal scale with values of 0, 1, 2, 3, 4, and 5), covariates, and sensitization. Covariates included recipient sex, age, ethnicity, diabetes, blood type, and prior kidney transplant. Interaction terms between each covariate and the number of homozygous HLA loci were also included. For the single and multivariable models, we only considered a covariate significantly associated with sensitization if the P < 0.05 for all sensitization groups (ie, mildly, highly, and extremely sensitized groups).

All analyses were performed with R version 4.0.5. 26

We identified 147 465 kidney transplant candidates between 2014 and 2019 that met the inclusion criteria. This included 84 955 (57.6%) in the nonsensitized group (CPRA 0), 39 203 (26.6%) in the mildly sensitized group (CPRA 1-69), 10 995 (7.5%) in the highly sensitized group (CPRA 70-94), and 12 311 (8.3%) in the extremely sensitized group (CPRA 95-100). As expected, women were present at higher percentages in the highly and extremely sensitized groups ( Table 1 ). The percentage of Black candidates, the number of previous kidney transplants, and time on the waitlist increased progressively in each successively more sensitized group (P < 0.001).

Given homozygosity at a single HLA locus (HLA-A, -C, -B, -DR, or -DQ), we calculated the odds of presence in the mildly, highly, or extremely sensitized groups (as compared with the nonsensitized group) using multinomial logistic modeling. For most HLA loci and within most ethnic groups, we found that homozygotes had significantly higher odds of being present in the mildly sensitized, highly sensitized, and extremely sensitized groups ( Figure 1 ; Table 5 , SDC, http:// links.lww.com/TXD/A415). The magnitude of this association increased for each successively more sensitized group and tended to be stronger for homozygosity at HLA-B and -DR than at HLA-A, -C, and -DQ.

The median number of homozygous HLA loci in the study cohort was 1. Most candidates in the study cohort (83 814 or 56.8%) exhibited homozygosity at 1 or more HLA loci, and homozygosity for 2 or more loci was frequent (35 312 or 23.9%) ( Table 2 ). The percentage of candidates in the highly sensitized and extremely sensitized groups generally increased with a progressively higher number of homozygous HLA loci. The percentage of Black candidates decreased from the 0 homozygous loci group to the 5 homozygous loci group, whereas the percentage of White and Asian candidates increased. The percentage of candidates with type 1 diabetes mellitus or a previous kidney transplant increased with a progressively higher number of homozygous HLA loci.

Other demographic factors were similar between candidates grouped by the number of homozygous HLA loci. We further hypothesized that candidates having multiple homozygous HLA loci would have an increased likelihood of sensitization. Given the number of homozygous HLA loci, we calculated the odds of presence in the mildly, highly, or extremely sensitized groups (as compared with the nonsensitized group) using multinomial logistic modeling. Generally we found that homozygotes at multiple HLA loci had significantly higher odds of being present in the mildly sensitized, highly sensitized, and extremely sensitized groups ( Figure 2 ; Table 6 , SDC, http:// links.lww.com/TXD/A415) and that the magnitude of the effect tended to increase with the number of homozygous loci. There were several exceptions: (1) Black candidates with 1, 4, or 5 homozygous HLA loci did not have a higher odds of being present in the mildly or highly sensitized groups and (2) Hispanic/ Latinx candidates with 1 or 5 homozygous HLA loci did not have a higher odds of being present in the mildly or highly sensitized groups. For the extremely sensitized group, there was a trend toward a decreased magnitude of the effect of homozygosity at multiple HLA loci on sensitization in Black candidates.

Women comprised a minority of the candidates in the study cohort (56 291 women, 38.2%) but a majority of the candidates in the highly and extremely sensitized groups (15 211 women, 65.2%). When assessed by ethnicity, Black women ( Figure 3A ) and Black men ( Figure 3B ) showed a higher percentage of candidates in the highly and extremely sensitized groups as compared with the other ethnic groups.

The study cohort was further divided into 3 groups by the number of homozygous HLA loci: candidates with 0 or 1 homozygous HLA loci (112 152 or 76.1%), candidates with 2 or 3 homozygous HLA loci (31 761 or 21.5%), and candidates with 4 or 5 homozygous HLA loci (3641 or 2.5%). We crosstabulated the proportion of individuals in each homozygosity group (ie, 0 of 1, 2 of 3, or 4 of 5 loci) and sensitization group (non, mildly, highly, and extremely sensitized) by sex and ethnicity. For both women and men of all ethnic groups (Figure 4) , there was a higher frequency of candidates with 2 of 3 and 4 of 5 homozygous loci in the mildly, highly, and extremely sensitized groups as compared with candidates with 0 of 1 homozygous HLA loci (P < 0.001). Women displayed a higher relative abundance of homozygotes at multiple HLA loci in sensitized groups as compared with men, with attenuation of this effect in Black candidates. For women, the relative abundance of candidates with 4 of 5 homozygous loci in the mildly, highly, and extremely sensitized groups (as compared with the nonsensitized group) was higher for Asian (1.49-fold) and White candidates (1.28-fold) than Hispanic/Latinx candidates (1.19-fold), and lowest for Black candidates (1.15-fold). Men displayed an overall lower relative abundance of candidates with 4 of 5 homozygous loci in sensitized groups, but relative abundance was higher for Hispanic/Latinx (1.32-fold) and White candidates (1.24-fold) than Asian candidates (1.16-fold), and again lowest for Black candidates (1.04-fold). 

Based on the preceding analyses, we sought to identify factors independently associated with sensitization. Covariates were analyzed in single variable multinomial models. We also included an interaction between each covariate and the number of homozygous HLA loci (assessed on an ordinal scale with values of 0 to 5). We found that the number of homozygous HLA loci, female sex, Black ethnicity, and a history of prior kidney transplant were all associated with an increased odds of presence in the mildly, highly, and extremely sensitized groups as compared with the nonsensitized group ( Table 7 , SDC, http://links.lww.com/TXD/A415). Female sex, Black ethnicity, and a history of prior kidney transplant also displayed a significant positive interaction with the number of homozygous HLA loci. In contrast, increasing age and diabetes type 2 were associated with a decreased odds of presence in the mildly, highly, and extremely sensitized groups. Increasing age displayed a significant positive interaction with the number of homozygous HLA loci.

A multivariable model was then constructed using these factors, including their interaction, with the number of homozygous HLA loci (Table 3 ). In this model, we found that the number of homozygous HLA loci remained significantly associated with an increased odds of presence in the mildly sensitized (OR 1.08/homozygous locus, 95% CI 1.03-1.14, P = 0.002) and extremely sensitized groups (OR 1.10/homozygous locus, 95% CI 1.00-1.20, P = 0.044), but not in the highly sensitized group (OR 0.96/homozygous locus, 95% CI 0.87-1.05, P = 0.383). Female sex, Black ethnicity, and a history of prior kidney transplant remained associated with an increased odds of presence in each progressively more sensitized group. Of these, female sex was the only factor displaying an significant interaction with HLA homozygosity, such that increasing number of homozygous HLA loci was associated with an increased odds of presence in the highly (OR 1.07/homozygous locus, 95% CI 1.02-1.11, P = 0.004) and extremely sensitized groups (OR 1.15/homozygous locus, 95% CI 1.11-1.21, P < 0.001).

In this study, we assessed the association between HLA homozygosity and sensitization. We found that homozygosity at HLA-A, -C, -B, -DR, and -DQ was associated with sensitization, and the magnitude of this effect varied by the specific locus. More significantly, we found that as the number of homozygous loci increased, the odds of being sensitized, especially highly sensitized or extremely sensitized, increased. The magnitude of this effect varied by ethnicity, with a lower magnitude of this effect in Black candidates. Women comprised a majority of the highly and extremely sensitized candidates and we observed a higher relative abundance of women candidates with homozygosity at multiple HLA loci as compared with men. In a multivariable model, the number of homozygous HLA loci was associated with an increased odds of presence in the mildly and extremely sensitized groups, but not in the highly sensitized group. These differences are likely attributable to the significant interaction between female sex and HLA homozygosity. In contrast, other factors associated with sensitization, including recipient ethnicity and a history of prior kidney transplant did not interact with HLA homozygosity.

In studies of apheresis donors, only a small percentage (<10%) of women without a history of pregnancy are sensitized. 5, 13, 14 End-stage renal disease has also not been associated with sensitization in the absence of other sensitizing events. 28 In this study, we have used female sex as a surrogate marker of previous pregnancy, as parity is not available for transplant candidates in the UNOS dataset. We found that the number of homozygous HLA loci interacted only with female sex to increase the likelihood of sensitization, suggesting that HLA homozygosity is an innate factor that seems to enhance the effect of pregnancy-related sensitization.

We found that mildly, highly, and extremely sensitized Black candidates, who comprised a larger percentage of these groups compared with other ethnicities, were enriched for candidates possessing multiple homozygous HLA loci at a lower magnitude compared with White, Hispanic/Latinx, and Asian candidates. HLA haplotypes are strongly related to ethnicity and the Black population is well known to have higher HLA heterozygosity. 29 Although we observed a strong relationship between Black ethnicity and an increased odds of presence in each progressively more sensitized group, ethnicity did not interact with the number of homozygous HLA loci. These findings suggest that HLA homozygosity is not a mediator of the increased burden of sensitization faced by Black candidates.

The biological mechanisms responsible for the higher burden of HLA sensitization in Black kidney transplant candidates remain unclear. Differences in B cell subsets and B cell receptor (BCR) signaling have been demonstrated in healthy lymphocyte donors as well as patients with systemic lupus erythematosus of African American ancestry. 30, 31 Importantly, polymorphism at the immunoglobulin heavy chain locus is extreme 32 and may also contribute to ethnicity-specific differences in humoral response, as has been noted after influenza vaccination. 33 Given that highly and extremely sensitized Black candidates have diminished access to kidney transplant as compared with similarly sensitized White candidates, 34 further research is urgently needed to define the biologic mechanisms of sensitization in Black candidates.

The mechanism by which HLA homozygosity promotes sensitization is not established. During B cell development, FIGURE 5 . Proposed model for the mechanism of HLA homozygosity mediated sensitization. We hypothesize that increased HLA homozygosity leads to a less diverse repertoire of self-HLA on the cell surface, which in turn leads to less "pruning" of B cells with HLA-specific receptors, ultimately resulting in a larger number or breadth of HLA antibodies. BCR, B cell receptor.

V/D/J and V/J genes are randomly recombined to generate the heavy and light chains of the BCR, respectively. 35 As a result of this stochastic process, autoreactivity of the BCR is common. 36 Mechanisms for tolerizing autoreactive B cells include receptor editing, induction of anergy, and clonal deletion. 37 Receptor editing, 38 the process by which the light chain gene undergoes a secondary V/J recombination and the heavy chain gene undergoes replacement, seems to be the major mechanism of tolerance for membrane proteins such as HLA. 39, 40 We hypothesize that during B cell development in the bone marrow, increased HLA homozygosity leads to a less diverse repertoire of self-HLA on the cell surface, which in turn leads to less "pruning" of B cells with HLA-specific B cell receptors. Pruning of B cells is likely to occur via receptor editing. This results in a larger number and breadth of HLA-specific B cells, and a downstream larger number and breadth of HLA antibodies ( Figure 5 ). In this way, sensitization related to HLA homozygosity is not due to a defect in tolerance per se, but a "loophole" in tolerance attributable to a limited repertoire of self-HLA epitopes. In support of this hypothesis, patients with systemic lupus erythematosus, which is characterized by pathologically decreased BCR editing, 41 have been found to have elevated levels of HLA antibodies. 42, 43 Further studies are needed to verify this hypothesis.

Interestingly, although we observed that a history of kidney transplant was strongly associated with sensitization, HLA homozygosity did not enhance its effect. We postulate that the mechanisms of transplant-related sensitization may be distinct from those of pregnancy-related sensitization. More specifically, we postulate that the proinflammatory cytokine milieu of transplant rejection may lead to bypass of normal tolerance mechanisms, making the recipient's HLA genotype irrelevant in this context. In support of this hypothesis, the ratio of interleukin-10 to tumor necrosis factor-α expression by transitional B cells is a powerful marker of cellular rejection, 44 and autoantibodies have been found to be increased during acute humoral/mixed rejection after kidney transplant. 45 In contrast, pregnancy is a protolerogenic state, characterized by a decrease in the number of circulating transitional B cells, 46 presumably leading to preservation of normal tolerance mechanisms and antibody development in relation to the recipient's HLA genotype.

To the best of our knowledge, HLA homozygosity has not previously been identified as a factor contributing to sensitization in solid organ transplant candidates. Because HLA genes are highly polymorphic, 18 homozygosity occurs at a frequency of 10%-30% for each locus. Thus, a large cohort is needed to observe the relationship between HLA homozygosity and sensitization, especially when considering candidates who have homozygosity at multiple HLA loci. Our use of a cohort of 147 461 patients facilitated our ability to identify the associations reported here.

This study has several important limitations that merit discussion. First, there were a significant number of candidates that were excluded due to missing typing at the HLA-C and -DQ loci. Omission of these candidates could lead to skew in the cohort. Reassuringly, we found that the frequency of HLA homozygosity was similar in our cohort as compared with NMDP for Whites, Blacks, and Hispanics. We did find a higher percentage of homozygotes at all HLA loci in Asian candidates in UNOS as compared with NMDP. This could be due to differences in split versus broad antigen reporting, as Asian candidates displayed a higher percentage of homozygosity related to split antigens ( Table 1 , SDC, http://links. lww.com/TXD/A415), or could be due to differences between these databases in population substructure.

Next, there are several factors that can affect the accuracy of CPRA as the metric of a candidate's level of sensitization. The criteria utilized for designating UA-HLA vary between HLA laboratories, 47 and as such CPRA values could underestimate a candidate's level of sensitization at transplant centers with high thresholds. Likewise, we focused on HLA-A, -C, -B, -DR, and -DQ, and did not investigate the role of the HLA-DP locus. Inclusion of HLA-DP UA-HLA has been shown to increase CPRA values, especially in highly sensitized candidates. 48 Additionally, single antigen bead assays may miss rare specificities that are not present on the beads. 49 Our analysis was based on low-resolution (antigen level) typing available in the OPTN database. Assessing candidate HLA typing at the allelic level could allow for characterization of the effect of interallelic distance on sensitization as a continuous rather than dichotomized (eg, homozygous versus heterozygous) quantity. Granular data on the stimuli for sensitization, for example, parity and history of transfusion, were not available in the database. Such data could lead to an improved understanding of how alloimmune stimuli lead to the development of HLA antibodies in the context of HLA homozygosity. Last, HLA antibody profiles change over time and our use of maximum CPRA during listing may introduce bias.

In summary, we have found that HLA homozygosity increases the likelihood of sensitization in kidney transplant candidates. These results are particularly relevant to women as they comprise the majority of highly and extremely sensitized kidney transplant candidates and there is a specific interaction between the number of homozygous HLA loci and female sex, presumably via pregnancy. Thus, HLA homozygosity is an innate factor that seems to enhance the effect of pregnancyrelated sensitization. Further research is needed to identify the immunologic mechanisms that underlie this observation.

Measuring and monitoring equity in access to deceased donor kidney transplantation

Pregnancy-induced sensitization promotes sex disparity in living donor kidney transplantation

Sensitization from transfusion in patients awaiting primary kidney transplant

Red blood cell transfusions and the risk of allosensitization in patients awaiting primary kidney transplantation

The effect of previous pregnancy and transfusion on HLA alloimmunization in blood donors: implications for a transfusion-related acute lung injury risk reduction strategy

Frequency and determinants of pregnancy-induced child-specific sensitization

A lifetime versus a graft life approach redefines the importance of HLA matching in kidney transplant patients

Comprehensive assessment of sensitizing events and anti-HLA antibody development in women awaiting kidney transplantation

CPRA for allocation of kidneys in the US: More candidates ≥98% CPRA, lower positive crossmatch rates and improved transplant rates for sensitized patients

Calculated panel-reactive antibody predicts outcomes on the heart transplant waiting list

Association between allosensitization and waiting list outcomes among adult lung transplant candidates in the United States

Prevalence and risk factors of antibodies to human leukocyte antigens in haploidentical stem cell transplantation candidates: A multi-center study

Prevalence of HLA sensitization in female apheresis donors

Screening for HLA antibodies in plateletpheresis donors with a history of transfusion or pregnancy

Natural" human leukocyte antigen antibodies found in nonalloimmunized healthy males

Proinflammatory events are associated with significant increases in breadth and strength of HLAspecific antibody

Allo-HLA cross-reactivities of cytomegalovirus-, influenza-, and varicella zoster virus-specific memory T cells are shared by different healthy individuals

HLA population genetics in solid organ transplantation

Balancing selection and heterogeneity across the classical human leukocyte antigen loci: a meta-analytic review of 497 population studies

HLA heterozygote advantage against HIV-1 is driven by quantitative and qualitative differences in HLA allele-specific peptide presentation

Evidence for human leukocyte antigen heterozygote advantage against hepatitis C virus infection

Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy

Association of HLA class i genotypes with severity of coronavirus disease-19

HLA class I and II diversity contributes to the etiologic heterogeneity of non-Hodgkin lymphoma subtypes

Stem cell donor HLA typing improves CPRA in kidney allocation

R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing

Mapping molecular HLA typing data to UNOS antigen equivalents

Risk factors of sensitization to human leukocyte antigen in end-stage renal disease patients

Six-locus high resolution HLA haplotype frequencies derived from mixed-resolution DNA typing for the entire US donor registry

Racial differences in B cell receptor signaling pathway activation

B cells from African American lupus patients exhibit an activated phenotype

The immunoglobulin heavy chain locus: genetic variation, missing data, and implications for human disease

IGHV1-69 polymorphism modulates anti-influenza antibody repertoires, correlates with IGHV utilization shifts and varies by ethnicity

Association of racial disparities with access to kidney transplant after the implementation of the new kidney allocation system

The shape of the lymphocyte receptor repertoire: lessons from the B cell receptor

Predominant autoantibody production by early human B cell precursors

Mechanisms of central tolerance for B cells

B cell receptor editing in tolerance and autoimmunity

Receptor editing is the main mechanism of B cell tolerance toward membrane antigens

Tolerance induction to self-MHC antigens in fetal and neonatal mouse B cells

RS rearrangement frequency as a marker of receptor editing in lupus and type 1 diabetes

Increased alloreactive and autoreactive antihuman leucocyte antigen antibodies associated with systemic lupus erythematosus and rheumatoid arthritis

Increased frequency of class I and II anti-human leukocyte antigen antibodies in systemic lupus erythematosus and scleroderma and associated factors: a comparative study

Transitional B cell cytokines predict renal allograft outcomes

Increased autoantibodies against Ro/SS-A, CENP-B, and La/SS-B in patients with kidney allograft antibody-mediated rejection

Human pregnancy is accompanied by modifications in B cell development and immunoglobulin profile

HLA compatibility assessment and management of highly sensitized patients under the new kidney allocation system (KAS): a 2016 status report from twelve HLA laboratories across the

cPRA increases with DQA, DPA, and DPB unacceptable antigens in the Canadian cPRA calculator

Root cause analysis of limitations of virtual crossmatch for kidney allocation to highly-sensitized patients