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Table of Contents
REVIEW ARTICLE
Year : 2021  |  Volume : 15  |  Issue : 2  |  Page : 147-156

Pathobiology of Non-HLA immunity in renal transplantation


Department of Nephrology and Renal Transplantation, Virinchi Hospitals and Max Superspeciality Medical Centre, Hyderabad, Telangana, India

Date of Submission17-Jun-2020
Date of Acceptance30-Dec-2020
Date of Web Publication30-Jun-2021

Correspondence Address:
Dr. Praveen Kumar Etta
Department of Nephrology and Renal Transplantation, Virinchi Hospitals and Max Superspeciality Medical Centre, Hyderabad - 500 034, Telangana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_57_20

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  Abstract 

Conventionally, major histocompatibility complex (MHC)-encoded human leukocyte antigens (HLAs) of a donor are considered as the principal targets of the recipient's immune system in renal transplantation (RT), and the clinical significance of anti-HLA allo-antibodies (Abs) is well established. In contrast, the importance of non-HLA immunity in RT is being increasingly recognized. Majority of non-HLA immune targets are the non-MHC-encoded proteins on vascular endothelial cells and exist as cryptic autoantigens. The synergistic triad of tissue injury, anti-HLA, and non-HLA immunity is involved in many cases of graft rejection and loss. The exact mechanisms by which the non-HLA auto-Abs are produced and induce graft injury are still speculative and under research. Understanding them enables the development of novel diagnostic assays and therapeutic strategies and thereby improves long-term graft outcomes. In this review, we discuss the pathobiology and novel mechanisms of non-HLA immunity in RT.

Keywords: Human leukocyte antigen, nonhuman leukocyte antigens antibody, rejection, renal transplantation


How to cite this article:
Etta PK, Madhavi T, Parikh N. Pathobiology of Non-HLA immunity in renal transplantation. Indian J Transplant 2021;15:147-56

How to cite this URL:
Etta PK, Madhavi T, Parikh N. Pathobiology of Non-HLA immunity in renal transplantation. Indian J Transplant [serial online] 2021 [cited 2021 Jul 24];15:147-56. Available from: https://www.ijtonline.in/text.asp?2021/15/2/147/319890


  Introduction Top


Renal transplantation (RT) is the treatment of choice for majority of patients with end-stage renal disease.[1] Currently, acute and/or chronic antibody-mediated rejection (ABMR) plays a major role in graft dysfunction, leading to graft loss. The human leukocyte antigens (HLAs), which are encoded in the major histocompatibility complex (MHC) on the chromosome 6p, are considered as the most important allo-antigens (Ags). Anti-HLA antibodies (Abs) directed against donor (donor-specific Abs [DSAs]) have been involved in the majority of cases of ABMR. However, in a significant proportion of ABMR cases, HLA-DSAs cannot be identified either due to immunoadsorption by the graft or due to the presence of non-HLA Abs.[2] In the 2017 Banff schema, testing for non-HLA Abs was strongly advised in case of ABMR with no detectable HLA-DSAs.[3] The non-HLA Abs are being recognized as a cause for graft loss, due to reports of ABMR among grafts from HLA identical donors and/or in the absence of circulating HLA-DSAs.[4],[5],[6] Understanding the pathogenetic mechanisms underlying the production and the reactivity of non-HLA Abs is progressing currently, and this may enable the development of targeted therapies to improve both graft and patient survival. In this review, we discuss the recent developments in this field in relation to RT.


  Material and Methods Top


We reviewed published literature from PubMed database with the following search terms °∞non-HLA antibodies°±, °∞alloimmunity°±, °∞rejection°±, °∞renal transplantation°±, and °∞kidney transplantation°±. We identified 223 articles based on the search criteria. We included studies relevant to renal transplantation and of English language literature. After excluding abstracts, case reports, commentaries, Letters to editors, original articles which are not relevant or with insufficient data, we identified 84 articles/abstracts and reviewed full text of all selected articles.


  Types of Nonhuman Leukocyte Antigen Antibodies Top


Non-HLA Ags or minor histocompatibility Ags (mHAs) are non-MHC-encoded polymorphic proteins that are sufficiently antigenic to induce immune response when transplanted into a recipient with absent or altered expression. They have been extensively studied in HLA identical hematopoietic stem cell transplantation and are associated with graft-versus-host disease and graft-versus-leukemia effect but less in RT.[7] The genetic basis may be due to nonsynonymous single-nucleotide polymorphisms (nsSNPs) giving rise to polymorphic Ags, such as MHC class I-related chain A (MICA) Ags. The mHAs include various types of auto-Ags and allo-Ags and expressed on various cells such as vascular endothelial cells (VECs) and epithelial, parenchymal, and circulating immune cells. Numerous non-HLA Abs have been identified over the past few years, and they can be classified into three types [Table 1].
Table 1: Commonly identified nonhuman leukocyte antigens antigenic targets and antibodies

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  1. Allo-Abs direct against polymorphic Ags that differ between the recipient and donor. These are formed after exposure to allo-Ags in the form of previous transplants, pregnancies, and blood transfusions or formed de novo after RT, e.g., anti-MICA Abs
  2. Auto-Abs recognize self-Ags which are usually cryptic. These constitute the majority of non-HLA Abs. A significant proportion of them react with auto-Ags expressed by VECs. These anti-endothelial cell Abs (AECAs) include a spectrum of different Abs depending on Ags specificity such as anti-angiotensin-II type 1 receptor (AT1R) Abs, anti-endothelin-1 type A receptor (ETAR) Abs, anti-perlecan/LG3 Abs, and anti-agrin Abs
  3. Natural Abs (NAbs) exist in the absence of exogenous Ag exposure. They are polyreactive, e.g., anti-apoptotic cell Abs, and those against oxidation-related Ags (malondialdehyde [MDA]).



  Pathogenetic Mechanisms Top


The mechanisms by which non-HLA Abs are produced and induce rejection are not fully understood. Most of the non-HLA Ags are widely expressed throughout the body; this suggests that auto-Abs causing graft injury may act through specific mechanisms which require changes in the graft microenvironment.[8] In contrast to HLA, the non-HLA auto-Ags are usually cryptic. The auto-Ags are expressed whenever there is tissue (graft) injury, which can also result in the release of auto-Ags in the form of soluble Ags or extracellular vesicles (EVs). The development of neo-Ags through posttranslational modifications is also vital for the development of non-HLA Abs. The capability of Abs to mediate allograft injury may depend on their specificity and affinity, density of the target Ags, synergy with HLA-Abs, and presence of local graft permissive conditions. Both complement-dependent and complement-independent mechanisms play a role.

Tissue injury

Tissue (graft) injury is associated with various insults such as ischemia-reperfusion (IR), cytokine storm in deceased donor, hypoperfusion, vascular insults, surgical trauma, drug nephrotoxicity, infection, recurrent diseases, alloimmune response, and rejection and plays an important role in both inducing the production of non-HLA Abs and allowing them to bind to expressed cryptic Ags. Some of the non-HLA Abs such as anti-perlecan/LG3 Abs, AT1R-Abs, and NAbs can exist before RT and bind to their targets following tissue injury. The mechanisms underlying their production before RT are unclear. Vascular injuries in the form of vascular access creation and manipulation, and acute coronary and peripheral vascular events may play a role.[9]

Ischemia-reperfusion injury

Tissue injury due to IR stimulates innate inflammatory response contributing to the generation of alloimmune and autoimmune injury to the graft. It is associated with the generation of reactive oxygen species, complement activation, coagulation, VECs activation, and leukocyte recruitment. It triggers the release of EVs and damage-associated molecular patterns (DAMPs), including nucleic acids, histones, high mobility group protein B1, and other proteins. EVs serve as carriers of DAMPs and auto-Ags.[10] DAMPs can interact with pattern recognition receptors including Toll-like receptors 2 and 4 expressed on myeloid cells, dendritic cells, VECs, and tubular epithelial cells. This process activates the myeloid differentiation primary response protein 88 and nuclear factor kB (NF-kB) pathways, resulting in the production of proinflammatory cytokines, including IL-1β, IL-6, and TNF, which promote the activation of adaptive immune responses that can exacerbate allograft damage and further exposure to auto-Ags. The passive transfer of anti-LG3 Abs was found to aggravate delayed graft function (DGF) and acute kidney injury in a murine model of renal IR, partly through complement activation.[11] Oxidative stress and apoptosis may result in the formation of neo-Ags. The autoreactive Abs were shown to direct against Ags present in the renal pelvis, which is particularly sensitive to IR. Inflammation can also lead to upregulated HLA Ag expression. The microvascular damage leads to peritubular capillary dropout and enhanced renal fibrosis.

Alloimmune injury

Alloimmune response, once initiated, can spread to additional determinants within primary target Ags, and this process is termed “intramolecular epitope spreading.” The expansion of alloreactive T-cells to HLA Ags via the indirect recognition pathway is associated with chronic rejection and linked to the generation of HLA-DSAs. Similarly, it can also promote the development of autoreactive T- and B-cells that contribute to the rejection. Alloimmune graft injury creates permissive conditions for the enhanced availability of cryptic Ags.[12] Preexisting circulating auto-Abs bind to their targets and increase vascular inflammation. Ag mimicry between auto-Ags and donor MHC peptides may also play a role in triggering autoimmunity. Once autoreactive T-cells are generated, chronic stimulation of these cells can lead to epitope spreading, which has been reported to contribute to the generation of auto-Abs.

Graft-derived extracellular vesicles

Vascular and tissue injury triggers the release of EVs which express intracellular proteins/auto-Ags on their surface. Depending on their cellular source, EVs contain mRNAs, miRNAs, DNA, proteins, lipids, and carbohydrates and can modulate immune responses. The EVs can be of different types: exosomes, microparticles, and apoptotic bodies, all of which contain numerous auto-Ags.[8] Principally, auto-Ags presentation to recipient autoreactive T-cells by EVs may happen in three ways [Figure 1].
Figure 1: Autoantigen presentation by extracellular vesicles. EVs: extracellular vesicles, MHC: major histocompatibility complex, APC: antigen-presenting cell

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  1. Direct pathway: EVs containing MHC molecules complexed to auto-Ags can directly activate recipient T-cells. This is much less efficient process
  2. Indirect pathway: EVs can be internalized by recipient antigen-presenting cells (APCs), and the processed donor Ags can be presented to recipient T-cells
  3. ”Cross-dressing” of the recipient APCs with donor MHC: Cross-dressing occurs when EVs are internalized and recycled to the surface of recipient APCs without peptide-MHC reprocessing or when EVs are captured and fused to the APC surface. They can also activate recipient T-cells.


Experimental studies have shown the presence of high levels of LG3 fragment of perlecan in EVs, and injection of these vesicles induced the production of LG3-Abs and rejection. These vesicles contain active 20S proteasome complex, which prompts the production of auto-Abs. Bortezomib was used to block the production of LG3 auto-Abs triggered by EVs.[13]

Th17 cells and tertiary lymphoid tissue

Tertiary lymphoid tissue (TLT) is the ectopic accumulation of lymphoid cells (lymphoid neogenesis) in states of chronic inflammation. TLT and Th17 cells support the proliferation and maturation of autoreactive B-cells and auto-Abs production.[14] Under proinflammatory conditions, TLT is constantly fed neo-Ags released by tissue injury, leading to the production of pathogenic auto-Abs. Th17 cells secrete several effector molecules including IL-21, IL-22 and IL-17. Production of IL-17 leads to leukocyte recruitment, resulting in graft damage and release of auto-Ags. IL-21 can trigger formation of TLT and mediate B-cell differentiation and Ab class switch. The loss of self-tolerance may be further facilitated by impaired deletion of immature autoreactive B-cells through increased Th17 generation.

Loss of self-tolerance

Graft injury creates an inflammatory milieu that causes breakdown of B-cell tolerance and sets stage for the development of Abs against various kidney tissue Ags, some of which undergo posttranslational modifications. Cross-reactivity between infectious agents and self-peptides can also lead to activation of autoreactive B- and T-cells.

Nonhuman leukocyte antigen antibody-mediated graft damage

The auto-Abs may act through specific mechanisms requiring local graft permissive conditions such as HLA immune response or IR. Abs may activate the complement cascade and cause damage. Abs can induce lysis of target cells through activation of natural killer (NK) cells, by a process known as Ab-dependent cell-mediated cytotoxicity (ADCC). Ab binding can also induce VEC activation/injury and subsequent immune response.

Three-way relationship and synergy

Current experimental and clinical data support the concept of a three-way relationship and synergy between tissue injury, anti-HLA, and non-HLA immunity in enhancing graft damage [Figure 2]. IR and anti-HLA immune insults can cause endothelial injury and trigger the release of EVs that prompt auto-Abs production. Preexisting auto-Abs may recruit and bind to unmasked cryptic auto-Ags. Conversely, the inflammatory response induced by non-HLA Abs could sequentially upregulate HLA expression and increase the risk to develop HLA-DSAs. This hypothesis is supported by several studies that showed worst outcome in patients with both anti-HLA and non-HLA Abs.[15],[16]
Figure 2: Interrelation and synergistic triad of tissue injury, anti-HLA, and non-HLA immunity. IR: ischemia-reperfusion, DAMPs: damage-associated molecular patterns, PRRs: pattern recognition receptors, TLRs: toll-like receptors, ADCC: antibody-dependent cell-mediated cytotoxicity, HLA: human leukocyte antigen, TLT: tertiary lymphoid tissue

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Activation of complement cascade

Serum IgG molecules can be divided into four subclasses (IgG1–4) with varying capacity to activate complement and recruit effector cells through the Fc receptors (IgG3 > IgG1 > IgG2 > IgG4). IgG1 and IgG3 subclasses of Abs can fix C1q and trigger activation of complement cascade. Sublytic amounts of complement may activate VECs and induce proinflammatory condition. Some of the non-HLA Abs such as anti-LG3, anti-MICA, AECAs, NAbs, anti-vimentin Abs, and less commonly AT1R-Abs can act through complement-dependent pathways and induce graft injury/ABMR with positive C4d staining. However, in majority (up to 60%) of cases, non-HLA Abs result in C4d-negative ABMR.[17]

Vascular endothelial cells and natural killer cells

Non-HLA Abs binding may induce activation of VECs and intracellular signaling cascades. Activation of the phosphatidyl inositol 3 (PI3)-kinase pathway and the downstream Akt kinase appears to be central to VECs activation triggered by Abs. RhoA activation mediates PI3-kinase-dependent proliferation of human VECs.[18] Mammalian target of rapamycin inhibitors documented to be effective on endothelial activation and preliminary data over the efficacy of sirolimus and everolimus exist for AT1R-Abs and ETAR-Abs.[19] Abs can induce endothelial damage and enhance migration of vascular smooth muscle cells (VSMCs) from the media and facilitate development of obliterative vasculopathy in muscular vessels. Anti-LG3 Abs were identified as enhancers of endothelial damage and neointima formation and as novel regulators of obliterative remodeling associated with vascular rejection. Endothelial cell apoptosis is also crucial for the production of matricryptic fragments, which may led to the production of Abs such as anti-LG3 Abs. As mentioned, NK cells activation via ADCC can induce lysis of target cells.[20]


  Specific Mechanisms Top


The specific pathogenetic mechanisms of few well-characterized non-HLA Abs are discussed and are presented in [Table 2].
Table 2: Common nonhuman leukocyte antigens antibodies and their putative pathogenetic mechanisms

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Anti-endothelial cell antibodies

They are directed against a variety of Ags expressed on VECs such as MICA, AT1R, ETAR, perlecan/LG3, and H-Y Ags.[31] The commonly identified and well-characterized AECAs are described separately later. Brasile et al. reported for the first time the existence of pretransplant AECAs that caused hyperacute rejection of two successive grafts in a RT recipient (RTR).[32] Few of the Ags on the VECs are expressed in quiescent state and few, following endothelial damage.[33] The AECAs may be more pathogenic in the setting of deceased donor RT as those donors might express higher levels of ligands than those from living donors. A study of living donor RTs showed that pretransplant AECAs were not associated with AR or inferior graft function.[21] This suggests that the pathogenicity of the auto-Abs is also depend on several other factors such as ligand expression, IR injury, or inflammation within the allograft. The expression of ligands may vary depending upon their anatomical location, vessel type, and inflammatory milieu. AECAs may fix complement and show C4d positivity; however, in a significant proportion of cases, they can lead to C4d-negative ABMR. These could be due to the presence of noncomplement-fixing subclasses (IgG2 and IgG4) of Abs. In vitro, AECAs stimulated VECs, increased adhesion molecule expression, stimulated production of inflammatory cytokines, amplified the alloimmune response, and increased microvascular damage. Most initial studies have used western blotting and enzyme-linked immunosorbent assay (ELISA) to investigate the presence of AECAs. Recently, AECAs are being evaluated by flow cytometry (using donor peripheral blood endothelial precursor cells), indirect immunofluorescence (using human umbilical vein endothelial cells), and high-density protein arrays.[22],[34],[35]

Major histocompatibility complex class I-related chain A

MICA Ags are expressed on the surface of the VECs, epithelial cells, dendritic cells, fibroblasts, keratinocytes, and monocytes, but not on the surface of lymphocytes. The MICA gene locus is located on chromosome 6 in close linkage equilibrium to the HLA-B locus and is highly polymorphic with more than 105 alleles identified. Ab formation against polymorphic allo-Ags such as MICA was thought to be related to the same sensitizing events as for HLA-Abs (previous transplantations, blood transfusions, and pregnancies). However, several studies did not report this association. The formation of these Abs may be due to the cross-reactivity with other Ags such as infections.[36] MICA A5.1 mutation in the donor, which is related to the MICA*008 allele, is associated with increased MICA expression on donor VECs, and these may become important antigenic targets.[37] In addition, mismatching on certain amino acid residues leads to increased MICA Abs formation, and these structures are more accessible for Abs.[38] Under normal conditions, MICA expression is not detectable on quiescent VECs. Cellular stress conditions including inflammation, infection, and hypoxia induce MICA expression on VECs and other cells. The MICA Ags act as ligands for the activating C-type lectin-like receptor (NKG2D) which is expressed on NK cells, γδ T-cells, and CD8+ αβ T-cells. Interaction of MICA with NKG2D leads to the activation of cytotoxic T-lymphocytes and NK cells.[23] MICA-Abs are polyspecific; positive sera react against five different MICA Ags specificities on average.[39] The pathologic potential of MICA Abs could be mediated through complement fixation, and they have been associated with C4d-positive ABMR.

Several studies noticed that the association of MICA Abs with graft rejection was better observed in patients who received grafts well matched for HLA.[24],[40] Narayan et al. stated that anti-MICA Abs can be associated with both ABMR and acute cellular rejection (ACR), and they emphasized the need for serial quantification of MICA mean fluorescence intensity levels.[41] A recent Indian study found MICA Abs in 14.6% of pretransplant samples and concluded that preformed MICA Abs independently increased the risk of rejection.[42] As MICA is not expressed on resting lymphocytes, they cannot be detected with classical lymphocyte cross-matching. Alternatively, cytotoxicity assay using activated lymphocytes can be performed. Two different single antigen Luminex assays are available that detect Abs against 28 and 11 MICA Ags specificities covering approximately 94%–98% and 90% of the common Ags, respectively (LABScreen MICA Single Antigen).[43] MICB is also found to occur more frequently in rejected patients than in those with functioning grafts in RTRs.[44] Systematic MICA and MICB genotyping may be required to define an MIC mismatch in a donor-recipient pair.

Angiotensin II type 1 receptor

The AT1R is a transmembrane G-protein coupled receptor (GPCR), which has seven transmembrane domains. It is expressed on VECs, VSMCs, podocytes, and other kidney tissues. Angiotensin-II (AT-II) acts through AT1R and regulates blood flow, salt and water retention, aldosterone secretion, inflammation, and vascular remodeling. AT1R Abs exert an agonistic effect. Hyperactivity of AT1R causes hypertension, vasoconstriction, and VSMCs proliferation. In experimental studies performed in transplanted rats, following AT1R Abs infusion, signs of endarteritis and intravascular infiltrates were noted in their allografts but not in native kidneys. IR injury may modulate AT1R expression or its conformation to facilitate interactions with AT1R Abs. In vitro studies have shown that anti-AT1R Abs can induce Erk signaling in VECs and VSMCs, resulting in the increased expression of inflammatory and coagulation proteins. They can activate the transcription factors, activator protein-1 and NF-kB, in VECs and VSMCs. The resulting effects on gene transcription lead to increase in the production of proinflammatory cytokines. In addition, increased tissue factor expression and thrombotic occlusion were observed. AT-II also has direct effects on immune function. Stimulation of T-cells and other immune cells by AT-II and AT1R agonistic Abs increases the production of proinflammatory cytokines.[25]

Dragun et al. were the first to show that the IgG1 and IgG3 subclasses of anti-AT1R Abs were associated with a severe acute vascular rejection with malignant hypertension.[45] In one study, authors have observed a correlation between antibody strength (>17 U/ml) and ABMR.[46] Another study found that patients with anti-AT1R Abs level >9 U/ml run a higher risk of graft failure and worse histological grade of rejection.[47] Patients with both AT1R Abs and HLA-DSAs had greater incidence of allograft damage and graft loss than those with DSAs alone, suggesting a synergistic effect of these Abs.[16],[26] In a multicenter, observational cohort study, AT1R-Ab–positive patients had a significantly higher incidence of ACR.[48] In contrast, In et al. have not observed this correlation with ACR.[49] Compared to DSA-mediated rejection, AT1R Ab-associated rejection had a higher prevalence of hypertension, more vascular rejection with arterial inflammation, higher levels of endothelial-associated transcripts, and lack of complement deposition.[50] Majority of AT1R Abs were identified as IgG1 and IgG3 isotypes, yet C4d deposition was rare, suggesting a major role for complement-independent pathways.[51] A standardized solid phase assay using sandwich ELISA methodology for the detection of AT1R Abs has been validated for testing RTRs.[46] Several studies have documented efficacy of various therapies such as PLEX, IVIG, and RTX in anti-AT1R Ab–positive rejections.[45],[52],[53] ARBs such as losartan have also been used to block the activity of AT1R in these patients.[54]

The expression of AT1R in podocytes suggests a possible pathogenic role of AT1R Abs in glomerular pathologies. AT1R Abs were reported in a RTR diagnosed with ABMR and collapsing focal segmental glomerulosclerosis (FSGS) with severe podocyte effacement.[55] In another study, significantly higher levels of pretransplant AT1R Abs were observed in recipients with FSGS recurrence.[56] Anti-AT1R Abs are also considered to play a role in the pathophysiology of several vascular diseases, including preeclampsia, malignant hypertension, pulmonary arterial hypertension (PAH), and systemic sclerosis.

Endothelin-1 type A receptor

VECs and renal epithelial cells produce endothelin-1 (ET-1) which plays a role in blood pressure regulation. ET-1 can bind to two types of receptors: type A (ETAR) or B receptor. Similar to AT1R, ETAR is also a transmembrane GPCR and ETAR-Abs are agonistic Abs. They are capable of activating and damaging VECs. Binding of ET-1 to ETAR induces vasoconstriction and has mitogenic and proinflammatory effects. This process leads to obliterative vasculopathy and progressive tissue fibrosis. In one study, vasculopathy or arteritis were observed in patients with anti-ETAR titer ≥2.5 U/mL.[27] Single-nucleotide polymorphisms (SNPs) that were identified in both AT1R and ETAR were mainly associated with altered expression levels.[28],[57] An ELISA-based kit is available to test for ETAR-Abs. The pharmacologic antagonists at the ETAR are approved for the treatment of PAH, but their role in anti-ETAR Ab-mediated rejection has not been evaluated. In systemic sclerosis patients, activating ETAR Abs frequently occur coincidently with AT1R Abs.

Perlecan/LG3

Perlecan, a heparin sulfate proteoglycan, is a component of the vascular basement membrane (VBM). The C-terminal domain of perlecan (endorepellin) contains three laminin-like globular domains (LG3). Apoptotic VECs during vascular rejection liberate cathepsin L, which cleaves the LG3 domain from the endorepellin. Levels of circulating LG3 and anti-LG3 Abs showed a concomitant increase in patients with acute vascular rejection. Circulating LG3-Abs promotes microvascular injury partly through complement-dependent mechanisms. Microvascular damage leads to peritubular capillary dropout and enhanced renal fibrosis. Experimental studies suggested that LG3 causes vascular injury and neointimal formation by stimulating auto-Abs production and by promoting the migration of donor VSMCs or recipient-derived mesenchymal stem cells.[29] LG3 Abs have been involved in obliterative vascular remodeling during rejection.[30] Cardinal et al. reported that pre- and post-transplant levels of LG3 Abs of the IgG1 and IgG3 isotypes were significantly higher in RTRs with acute vascular rejection.[58] HLA-DSAs and LG3 auto-Abs may act synergistically to elicit graft injury.

H-Y antigen

H-Y Ags encoded by Y-chromosome in males and may cause rejection in male-to-female transplant.[59] H-Y–specific alloimmune T-cells have been detected in gender-mismatched transplantation.[60]

Agrin and vimentin

Agrin is a component of VBM and vimentin is an intracellular intermediate filament protein that can be expressed at the surface of apoptotic T-cells, neutrophils, and VECs. Vimentin is also secreted by macrophages, VECs, activated platelets, and neutrophils. There is growing evidence to show that the increased levels of auto-Abs to agrin and vimentin in patients with chronic rejection. They have the ability to fix complement and initiate proinflammatory effects.[61],[62] Mean anti-vimentin Ab levels were found to be elevated in patients with interstitial fibrosis and tubular atrophy and those with previously failed renal allografts.[63],[64]

Collagen-IV and fibronectin

Both the pretransplant and de novo development of auto-Abs to collagen-IV and fibronectin have been reported in RTRs diagnosed with transplant glomerulopathy (TG).[65] These patients displayed increased collagen-IV and fibronectin specific CD4+ T-cells that secreted IFN-γ and IL-17, as well as a reduction in IL-10 levels, which demonstrates tolerance break down to self-Ags.

Natural antibodies

NAbs react to multiple self-Ags and exogenous Ags as well as apoptotic cells. NAbs are often present at birth and are polyreactive by their ability to bind multiple different ligands such as nucleic acids, carbohydrates, proteins, and lipids. IgM NAbs are principally present in healthy individuals, but aberrant levels of IgG NAbs are detected in various autoimmune diseases and in transplantation. During IR, ischemic VECs expose self-Ags that may produce NAbs. IgG NAbs are predominantly of the complement-fixing IgG1 and IgG3 subclasses. Other mechanisms, including ADCC and VEC activation, may also play a role in rejection. Endothelial activation leads to proinflammatory effects and tissue damage. They also have synergistic action with HLA-DSAs. Indeed, four separate monoclonal NAbs have been isolated from RTRs and were found to cross-react to several HLA molecules, supporting synergism.[66]

NAbs bind to the Ags that are exposed at the surface of apoptotic cells such as phosphatidylserine and lysophosphatidylcholine. Increased apoptosis in the allograft during rejection was hypothesized to contribute to the class switching of B-cell clones reactive to apoptotic cells.[67],[68] Oxidation-related Ags resulting from lipid peroxidation as a response to oxidative stress are additional immune targets of NAbs. Peroxidation generates highly reactive products, such as MDA, that covalently bind to proteins or lipids. These adducts create neoepitopes recognized by NAbs. After RT, oxidative stress and local production of MDA have been described amid graft injury and chronic rejection. It is possible that damage to allograft stimulates lipid peroxidation, leading to oxidation-specific epitope exposure and subsequent NAbs development.[69],[70]

Other types of nonhuman leukocyte antigen antibodies

Sutherland et al. used protein microarray technology in pediatric RTRs during allograft rejection and found protein kinase Czeta (PKCζ) both within the renal tissue and infiltrating lymphocytes. Patients who had an elevated anti-PKCζ titer developed rejection, leading to graft loss. The authors opined that renal injury and inflammation associated with the rejection led to the immunological exposure of PKCζ with resultant Ab formation.[71] In another similar study, pretransplant Abs against peroxisomal trans-2-enoyl-CoA reductase were predictive of TG.[72] A more recent study found that auto-Abs against Rho GDP-dissociation inhibitor 2 were significantly associated with graft loss in deceased-donor RTRs but not in living donor recipients.[73] Other putative non-HLA Ags have been identified in several studies, but their significance is not conclusive. Some of them include Duffy antigen receptor for chemokines, human keratin 1, lamin B1, heat shock proteins, platelet-specific Ags, polymorphisms in chemokines and their receptors, glutathione S-transferase T1, and nucleolin.[74]

Nonhuman leukocyte antigen genetic mismatch, genomic collision, and other novel findings

Non-HLA genetic mismatches between RTRs and donors may predict long-term graft survival. Pineda et al. identified non-HLA mismatches based on exome sequencing data and found that they were significantly higher in patients with ABMR. They identified a set of 123 variants that were associated with the risk for ABMR.[75] In a recently published genome-wide analysis of 477 donor-recipient pairs, genetic mismatches in nsSNPs were quantified for genes encoding transmembrane or secreted proteins. The number of mismatches was predictive of graft loss after adjusting for HLA eplet mismatches.[76] Genetic variants that cause disruptions in kidney genes may predispose to allosensitization and rejection, particularly if the RTR is homozygous for the deletion polymorphism and receives an organ from a donor who has at least one normal allele. This is referred to as “genomic collision.” This was evaluated in a recent study that screened 705 RTRs for 50 common gene-disrupting deletion polymorphisms. Recipients who were homozygous for the specific SNP rs893403 at the LIM zinc finger containing protein 1 (LIMS1) locus had a higher risk of AR. They were associated with the presence of anti-LIMS1 Abs.[77] Several novel approaches such as proteomics are on-going in this field. Studies using protein arrays revealed a broad variety of non-HLA Ags associated with rejection and chronic allograft injury.[78],[79] In a recent study, Delville et al. identified 38 RTRs with acute microvascular rejection in the absence of anti-HLA Abs. Previously proposed AECAs against AT1R and ETAR or NAbs did not increase in these patients. Using a combination of transcriptomic and proteomic techniques, they were able to identify new endothelial targets for non-HLA Abs.[80]


  Conclusions Top


HLA Ags expressed on donor cells are the principal targets of the recipient's immune response, and the concept of ABMR has been linked traditionally to the HLA-DSAs. Mounting evidence has shown that various forms of non-HLA Abs play an important role in acute or chronic allograft rejection and portend negative long-term graft outcome. In many circumstances, the interrelation and synergistic triad of tissue (graft) injury, anti-HLA, and non-HLA immunity may cause allograft dysfunction, rejection, and reduced graft survival. The incomplete knowledge of the non-HLA Ags, mechanisms involved in the generation of Abs, autoimmunity, and graft injury hampers the management of these patients. A better understanding of pathobiology and identification of effector pathways would guide the path to the development of targeted therapies, thereby to improve long-term graft outcomes.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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