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. 2025 Sep 26;11(6):e70620. doi: 10.1002/vms3.70620

Unveiling Vasculature‐Associated Lymphoid Tissue (VALT) in Goats: A Novel Player in Kidney Inflammation

Md Abdul Masum 1,✉, Subrato Biswas 1, Rupa Akter 1
PMCID: PMC12466193  PMID: 41004130

ABSTRACT

Background and Objectives

Recently, we reported a uniquely developed tertiary lymphoid tissue around the blood vessels and named it vasculature‐associated lymphoid tissue (VALT) in nephritis model mouse kidneys. We established the role of VALT in the pathogenesis of kidney disease by providing immune effector cells. However, there are no reports concerning its occurrence in the goat kidney. Therefore, this study was designed to characterize the formation and activity of VALT in goats.

Method

Kidney samples from different goats were grouped into healthy kidney (HK), which showed normal structure, and inflamed kidney (IK), which showed glomerular hypertrophy, hypercellularity, mesangial matrix expansion, adherence of podocytes to parietal cells and tubular dilatation.

Result

Immunohistochemistry revealed infiltrating T cells, B cells and macrophages in both the glomerulus and tubulointerstitium of IK. Furthermore, cell clusters were observed in the perivascular area of the arcuate and interlobular arteries and veins of IK rather than HK, and these clusters were considered VALT. Cell characterization revealed that VALT was composed of T cells, B cells and macrophages and vascularized with numerous high endothelial venules. Juxtaposition of infiltrating lymphocytes and macrophages in VALT suggested possible antigen presentation to lymphocytes in situ. Moreover, the presence of Ki67+ proliferating cells and CD138+ plasma cells in VALT indicated its active immune status.

Conclusion

Therefore, we conclude that VALT develops in goat IK and participates in renal lesion development by providing effector cells.

Keywords: goat, kidney, renal lesions, tertiary lymphoid tissue, vasculature‐associated lymphoid tissue

Vasculature‐Associated Lymphoid Tissue (VALT) is a significant tertiary lymphoid tissue that contributes to kidney inflammation and has not yet been identified in ruminants. Our study revealed that VALT in goats consists of typical immune cells, including macrophages, T cells, B cells and high endothelial venules. Importantly, the presence of Ki67+ proliferating cells and CD138+ plasma cells in VALT indicates its active immune status. Therefore, VALT serves as a functional tertiary lymphoid tissue in goats, playing a role in kidney inflammation.

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1. Introduction

The freedom from diseases in mammals fully depends on the proper function of a sophisticated system called the lymphoid system. In adults, the mammalian body is decorated with secondary lymphoid organs (SLOs), which provide a microenvironment for the interaction between antigens and immune cells to induce effective immune responses (Aloisi and Pujol‐Borrell 2006). However, ectopic lymphoid tissue is formed in chronic inflamed non‐lymphoid tissue called tertiary lymphoid tissue (TLT), which shares most of the features of SLO (Pitzalis et al. 2014). General functions of TLT are clonal expansion, antigen presentation and production of autoantibodies against autoantigens and effector cells (Ruddle 2014; Van de Pavert and Mebius 2010). Importantly, the role of TLT can be either beneficial or detrimental, depending on the nature of the disease (Pitzalis et al. 2014).

TLTs are not encapsulated structures and are not formed in predetermined areas during embryogenesis like SLO (Van de Pavert and Mebius 2010). Rather, they are induced by inflammatory signals; therefore, they are formed in non‐lymphoid tissue where persistent inflammation occurs (Jones et al. 2016). Moreover, TLTs are formed in various tissues of non‐lymphoid organs, which fully vary among lymphoid tissue organizers, such as smooth muscle cells in atherosclerosis, joint capsule in arthritis and perivascular tissue in acute injured and lupus nephritis kidneys in humans and mice (Masum et al. 2020; Ruddle 2014; Van de Pavert and Mebius 2010). In addition, TLT has been reported to develop in the kidneys of pigs suffering from chronic leptospiral nephritis (Pezzolato et al. 2012). However, to our knowledge, there are no reports on TLT formation in the kidneys of small ruminants, such as goats.

Goats play a significant economic role by providing good quality meat, milk, fibre and skin (Mohanty et al. 2020). However, goat farming faces many problems, such as repeat breeding, infectious diseases and abortion, which have been widely investigated (Assefa et al. 2024; Rerkyusuke et al. 2024). Importantly, farmers keep goats for long periods of time for breeding purposes, but reports regarding aging‐related diseases, such as metabolic diseases or kidney diseases, are relatively scarce.

The kidney is a vital organ that filters metabolic wastes from the body and maintains body fluid homeostasis. It has been estimated that about 8%–10% of the general human population and about 1%–3% of all cats suffer from chronic kidney disease (Delanaye et al. 2017; Polzin 2011); however, kidney diseases are not uncommon in farm animals (Dutta et al. 2016). Moreover, several studies from abattoir inspection clearly showed the presence of histopathological renal lesions (RLs) in apparently healthy slaughtered goats (Ansari‐Lari 2007; Baghban and Yaripour 2016; Dutta et al. 2016; García‐Díez et al. 2023). Importantly, our previous studies showed that the development of histopathological features in the kidney is related to infiltrating immune cells in the kidney (Masum et al. 2019; Masum et al. 2018). Recently, we have clarified a TLT near the blood vessels of the kidney of mice, in which both vascular and perivascular structures play a role as lymphoid tissue organizers. We named this TLT ‘vasculature‐associated lymphoid tissue (VALT)’. Moreover, this VALT maintained the infiltrating immune cells in the kidney and was correlated with histopathological lesion development in the kidney (Masum et al. 2020). However, there are no reports on immune cell maintenance via TLT in goat kidneys.

In the present study, we have, for the first time, clarified a TLT, namely, VALT, in 1‐year‐old female goats that have most of the features and functions as found in our previously described VALT in the diseased kidneys of mice.

2. Materials and Methods

2.1. Experimental Animal

We used a total of 10 (N = 10) 1‐year‐old female Black Bengal goats from Bangladesh (Capra aegagrus hircus) for this experiment. The animals were examined physically and clinically at Sher‐e‐Bangla Veterinary Teaching Hospital, and they did not show any sign of abnormalities. After slaughtering, each animal's kidneys were also examined thoroughly and found to have no gross lesions. In addition, there were no gross lesions observed in other organs. We randomly collected kidneys, which were examined histopathologically. The kidneys that showed normal glomerulus and tubulointerstitium were considered healthy kidneys (HKs) (N = 6), and the kidneys that showed abnormal glomerulus and tubulointerstitium were considered inflamed kidneys (IKs) (N = 4).

2.2. Sample Collection

The goats were subjected to intramuscular sedation with xylazine (3.0 mg/kg body weight) followed by general anaesthesia with pentobarbital sodium (500 mg/kg body weight) through the intravascular route. The goats were sacrificed by intravenous administration of a saturated potassium chloride solution of at least 0.1 mL/kg. The jugular vein was exsanguinated after checking for the absence of the ocular reflex from goats (Underwood and Anthony 2020). They were thoroughly examined for the detection of any gross pathological lesions. The excised kidneys were sliced into small pieces (4–5 mm thickness) and immersed immediately in 10% neutral buffered formalin (Masum et al. 2017).

2.3. Histopathological Examination

Dehydration of kidney slices via the ascending group of alcohols was followed by clearing with xylene and blocking with paraffin. The paraffin blocks were cut to a thickness of 4 µm and stained with haematoxylin and eosin and periodic acid–Schiff haematoxylin for histopathological examination. Glomerular lesions (GLs) and tubulointerstitial lesions (TILs) were examined by periodic acid–Schiff haematoxylin staining (Masum et al. 2020).

2.4. Immunohistochemistry

Immunohistochemistry for CD3, CD20, IBA1, peripheral node addressin (PNAd), Ki67 and CD138 was performed to detect pan T cells, B cells, macrophages, high endothelial venules (HEVs) and plasma cells, respectively, as described in our previous study (Masum et al. 2020). A summary of the staining conditions is presented in Table 1.

TABLE 1.

Immunohistochemistry details.

Antibody Antigen retrieval Blocking Primary antibody, dilution Secondary antibody, dilution
CD3 TB 115°C, 15 min 10% NGS Rabbit polyclonal antibodies (Nichirei), 1:200 Goat anti‐rabbit (SABPO kit, Nichirei) (Biotinylated), 1:100
CD20 TB 115°C, 15 min 10% NGS Rabbit polyclonal antibodies (Spring Bioscience), 1:300 Goat anti‐rabbit (SABPO kit, Nichirei) (Biotinylated), 1:100
IBA1 0.1% pepsin 10% NGS Rabbit polyclonal antibodies (Wako), 1: 1200 Goat anti‐rabbit (SABPO kit, Nichirei) (Biotinylated), 1:100
PNAd TB 115°C, 15 min 10% NGS Rat polyclonal antibodies (Biolegend), 1: 500 Goat anti‐rat IgG (Caltag Medsystems) (Biotinylated), 1:100
Ki67 TB 115°C, 15 min 10% NGS Rabbit polyclonal antibodies (Abcam), 1: 800 Goat anti‐rabbit (SABPO kit, Nichirei) (Biotinylated), 1:100
CD138 CB 115°C, 15 min 10% NGS Rat monoclonal antibody (Biolegend), 1:300 Goat anti‐rat IgG (Caltag Medsystems) (Biotinylated), 1:100
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Abbreviations: CB, citrate buffer; NDS, normal donkey serum; NGS, normal goat serum; TB, tris buffer.

2.5. Scanning Electron Microscopy (SEM)

The sample was prepared for SEM as previously described (Masum et al. 2018). Briefly, to prepare paraffin blocks, kidney slices were fixed with 2.5% glutaraldehyde (GTA) and 4% paraformaldehyde for 4 and 12 h, respectively. Then, the paraffin blocks were cut to 10 µm thickness and mounted on a glass slide. The sections were deparaffinized, fixed and post‐fixed with 2.5% GTA and 1% osmium tetroxide for 2 and 1 h, respectively. Tissue sections were dehydrated and fixed on a mounting stub. The specimens were coated with an ion sputter (Hitachi; Tokyo, Japan) for 90 s and examined using an S‐4100 SEM (SU 8000, Hitachi) with an accelerated voltage of 10 kV.

3. Results

3.1. RLs Found in the Goat

Kidney sections from all goats were randomly examined by periodic acid–Schiff haematoxylin staining to preliminarily examine their histopathological state. There were no GLs or TILs in normal HKs (Figure 1A). GLs characterized by glomerular hypertrophy, hypercellularity, mesangial matrix expansion and adherence of podocytes to parietal cells were clearly observed in IKs (40%, n = 10) (Figure 1B). Moreover, IKs tended to show a wider lumen in the proximal tubules compared with HKs (Figure 1B). Immunohistochemistry for CD3, CD20 and IBA1 showed that T cells, B cells and macrophages were absent in both the glomerulus and tubulointerstitium of control HK (Figure S1A–F), but they were found in both GLs and TILs of IK (Figure 1C–H).

FIGURE 1.

FIGURE 1

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Development of renal lesions, kidney, goat. Periodic acid–Schiff haematoxylin (PAS‐H). (A). Healthy kidney (HK) shows normal glomerulus and tubulointerstitium. (B). Inflamed kidney (IK) shows glomerular hypertrophy and cellularity, mesangial matrix expansion, adherence of podocytes to parietal cells and tendency of tubular dilatation. (C). CD3‐immunolabeled T cells in the glomerulus of inflamed kidney. (D). CD20‐immunolabeled B cells in the glomerulus of inflamed kidney. (E). IBA1‐immunolabeled macrophages in the glomerulus of inflamed kidney. (F). CD3‐immunolabeled T cells in the tubulointerstitium of inflamed kidney. (G). CD20‐immunolabeled B cells in the tubulointerstitium of inflamed kidney. (H). IBA1‐immunolabeled macrophages in the tubulointerstitium of inflamed kidney. Inset: high magnification.

3.2. VALT Found in the Goat Kidneys

To determine if there were any cellular clusters in the kidney, we examined the goat kidney sections thoroughly using haematoxylin and eosin staining. In HK, there were no observable cellular clusters, especially in the perivascular connective tissue of the blood vessels (Figure 2A). However, IK showed the existence of prominent cellular clusters similar to those reported in mice (Masum et al. 2020), and based on our observations, we considered it to be a VALT (Figure 2B). Most of the VALTs were confined to the perivascular connective tissue of the arcuate and lobular arteries or veins that accompany them. We did not find any VALT near the interlobular artery or vein. SEM analysis showed that VALT was subdivided into chambers by connective tissue septa that harboured immune cells (Figure 2C).

FIGURE 2.

FIGURE 2

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Presence of vasculature ‐associated lymphoid tissue (VALT) in kidney, goat. Haematoxylin‐eosin (HE). (A). There is no cellular cluster (VALT) near blood vessel in normal kidneys. (B). Inflamed kidney shows the presence of cellular cluster (VALT) near blood vessel. (C). SEM examination shows immune cells are in the chambers of VALT made by connective tissue septa. Inset: high magnification.

3.3. Cellular and Vascular Characterization of VALT in the Goat Kidney

Our previous study showed that VALT is composed of T cells, B cells and macrophages in nephritis mouse kidneys (Masum et al. 2020). In the present study, we also found that VALT is composed of CD3+ T cells, CD20+ B cells and IBA1+ macrophages (Figure 3A–C). CD3+ T cells were the major infiltrating cells and were found throughout the VALT (Figure 3A). However, CD20+ B cells and IBA1+ macrophages were fewer/scarce in number compared to T cells and were scattered throughout the VALT (Figure 3C–D). The VALT was well vascularized with PNAd+ HEVs in the IK (Figure 3D).

FIGURE 3.

FIGURE 3

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Cellular composition and vascularization of vasculature‐associated lymphoid tissue (VALT), kidney, goat. Immunohistochemistry. (A). CD3‐immunolabeled T cells in VALT. (B). CD20‐immunolabeled B cells in VALT. (C). IBA1‐immunolabeled macrophages in VALT. (D). PNAd‐immunolabeled high endothelial venules in VALT. Inset: high magnification.

3.4. Contact Features Between T Cells and Macrophages in VALT

Our previous study suggested that antigen presentation takes place in the VALT of nephritis mouse kidneys by exhibiting a contact between lymphocytes and macrophages as well as certain gene expression (Masum et al. 2020). In the present study, we observed the contact features between T cells and macrophages to suggest possible antigen presentation. CD3+ T cells (Figure 4A) and IBA1+ macrophages (Figure 4B) were present in VALT. Moreover, they were located adjacent to each other (Figure 4C). SEM analysis also revealed juxtaposition of lymphocytes and macrophages in VALT (Figure 4D).

FIGURE 4.

FIGURE 4

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Juxtaposition of lymphocyte and macrophage in vasculature‐associated lymphoid tissue (VALT), kidney, goat. Immunofluorescence. (A). CD3‐immunolabeled T cells in VALT. (B). IBA1‐immunolabeled macrophages in VALT. (C). CD3‐immunolabeled T cells juxtapose to IBA1‐immunolabeled macrophages in VALT. (D). SEM examination shows juxtaposition of lymphocyte and macrophage in VALT. Inset: high magnification.

3.5. Immunological Activities of VALT

Ki67+ proliferating cells (Figure 5A) and CD138+ plasma cells (Figure 5B) were observed in VALT.

FIGURE 5.

FIGURE 5

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Activation and function of vasculature‐associated lymphoid tissue (VALT), kidney, goat. Immunohistochemistry. (A). Ki67‐immunolabeled proliferating cells in VALT. (B). CD138‐immunolabeled plasma cells in VALT. Inset: high magnification.

4. Discussion

TLT usually forms in inflamed non‐lymphoid tissue and participates in pathogen clearance or aggravation of lesions in respective organ (Masum et al. 2020; Neyt et al. 2012; Pitzalis et al. 2014; Van de Pavert and Mebius 2010; Yin et al. 2016). In the present study, we characterized fully developed TLT and VALT in goat IK, which provides a microenvironment for antigen presentation, cellular activity and antibody production.

First, our routine histological examinations showed the presence of GLs and TILs in 40% of the examined goats (n = 10). However, immunohistochemistry for CD3, CD20 and IBA1 showed T cells, B cells and macrophages in both GLs and TLs of IK. Most of the examined goats were apparently healthy, except for one that had a large abscess on the dorsal flank. Thus, RLs were clearly observed in apparently healthy goats. Importantly, previous studies have shown that kidneys from clinically healthy goats have gram‐negative and gram‐positive bacteria as well as histopathological lesions (Ansari‐Lari 2007; Baghban and Yaripour 2016; Dutta et al. 2016; Neyt et al. 2012). Moreover, small ruminants developed mesangiocapillary glomerulonephritis due to hypocomplementemia after 1 month of age, suggesting that maternal and environmental factors influence the development of GLs (Angus et al. 1980, 1974; Jarad et al. 2020). Therefore, we considered that RLs in the examined goats might have resulted from latent/secondary infection and maternal or environmental influences.

Next, we examined the presence of VALT in IK cells. We found VALT in the perivascular area of goat IK, and SEM analysis clearly showed the arrangement of VALT in goat, which was similar to that of nephritis mouse kidney (Masum et al. 2020), where connective tissue septa divide the VALT into many chambers containing immune cells. Cellular characterization of VALT in goat kidneys showed that it was composed of T cells, B cells and macrophages. Therefore, VALT is a TLT that develops because of inflammation. There are two possible mechanisms for VALT development in goats. First, microorganisms might be present in follicular dendritic cells in the kidney, resulting in chemokine secretion to stimulate lymphoid neogenesis, as shown in other studies (Pezzolato et al. 2012; Pitzalis et al. 2014). Alternatively, similar to our own and other previous studies, secondary renal inflammation could result in infiltration of inflammatory cells and inflammatory cytokine production in the kidney, which stimulates perivascular stromal cells to induce lymphoid neogenesis via lymphorganogenic chemokine production (Aloisi and Pujol‐Borrell 2006; Masum et al. 2020). Future studies targeting the initial events of VALT formation would be helpful in designing therapeutic targets, as shown in our previous study (Masum et al. 2020). In addition, green nutritional approaches with nanotechnology‐based feed materials and microorganisms are playing an important role in protecting from disease (Saeed et al. 2025, Saeed et al. 2025). Therefore, these approaches could also be promising to tackle kidney disease progression in small ruminants.

TLTs are usually accompanied by HEV and lymphatic vessels (Gräbner et al. 2009; Jarad et al. 2020; Ruddle 2016; Stock et al. 2019; Yin et al. 2016). However, the lymphatic vessel system of TLT has yet to be clearly elucidated (Stock et al. 2019). TLT may contain both HEV and lymph vessels; however, the absence of both HEV and lymph vessels has also been reported (Stock et al. 2019; Masum et al. 2020). In the present study, the VALT of goats was vascularized with HEV only. As shown in our previous study, VALT is different from nephritis kidneys in vascularization in goats. We reported that VALT in lupus nephritis kidney had lymph vessels and HEV‐forming molecules instead of HEV itself (Masum et al. 2020). Clarification of the difference in TLT lymphatic vasculature, in detail, would aid in understanding the immune cell trafficking from systemic circulation to VALT and vice versa in different disease statuses.

TLT functions as a local site for antibody production against locally produced antigens presented in VALT, resulting in activation and maturation of lymphocytes (Jones et al. 2016; Masum et al. 2020; Neyt et al. 2012; Pitzalis et al. 2014). In the present study, adjacently localized lymphocytes and macrophages were found in VALT. In addition, SEM analysis clearly revealed juxtaposed lymphocytes and macrophages in VALT. Importantly, our previous study showed juxtaposition of lymphocytes and antigen‐presenting cells/molecules as well as enrichment of genes related to antigen presentation, lymphocyte activation, and immunological synapse in VALT of a nephritis mouse model (Masum et al. 2020). Therefore, juxtaposition of lymphocytes and macrophages in the VALT of goat kidneys suggested the possibility of presentation of locally produced antigens to activated T cells in situ. We also found Ki67+ cells in the VALT, indicating the activation of local cells. Moreover, localization of CD138+ plasma cells was found in VALT, suggesting that VALT in goats could be related to antibody production against autoantigens in severe diseases. Notably, CD3+ T cells were predominant in VALT, GLs and TILs of IK among the examined immune cells. Therefore, we hypothesized that VALT could be correlated with RL development in goat IK by providing effector T cells.

5. Conclusion

In conclusion, inflammatory stimuli could activate the perivascular structures to secrete homeostatic chemokines for homing and organization of immune cells near blood vessels. A fully developed VALT provides a microenvironment for antigen presentation and perpetuation of antibodies and effector cells that might cause RL development in goat kidneys. Further studies with large samples of different renal diseases in goats would be beneficial to conclude the precise function of VALT in goat kidney diseases.

Author Contributions

Md. Abdul Masum: conceptualization, data curation, formal analysis, investigation, methodology, project administration, software, resources, supervision, validation, visualization, writing – original draft, writing – review and editing. Subrato Biswas: data curation, formal analysis, investigation, methodology, software, resources, writing – original draft, writing – review and editing. Rupa Akter: data curation, investigation, methodology, software, resources, writing – original draft, writing – review and editing. All authors gave final approval for publication and agreed to be held accountable for the work performed therein.

Ethics Statement

The investigators adhered to the Animal Welfare and Experimentation Ethics Committee of Sher‐e‐Bangla Agricultural University (SAU), Dhaka‐1207, Bangladesh (Approval no. SAU/AHIPHI/22/845).

Conflicts of Interest

The authors declare no conflicts of interest.

Peer Review

The peer review history for this article is available at https://publons.com/publon/10.1002/vms3.70620.

Supporting information

Figure S1: Inflammatory status of control goat kidney. Immunohistochemistry. (A) Absence of CD3‐immunolabeled T cells in the glomerulus of control kidneys. (B) Absence of CD20‐immunolabeled B cells in the glomerulus of control kidneys. (C) Absence of IBA1‐immunolabeled macrophages in the glomerulus of control kidneys. (D) Absence of CD3‐immunolabeled T cells in the tubulointerstitium of control kidneys. (E) Absence of CD20‐immunolabeled B cells in the tubulointerstitium of control kidneys. (F) Absence of IBA1‐immunolabeled macrophages in the tubulointerstitium of control kidneys.

VMS3-11-e70620-s001.jpg (512.1KB, jpg)

Acknowledgements

The authors acknowledge Professor Dr. Osamu Ichii, and Professor Dr. Yasuhiro Kon for their suggestion and support.

Masum, M. A. , Biswas S., and Akter R.. 2025. “Unveiling Vasculature‐Associated Lymphoid Tissue (VALT) in Goats: A Novel Player in Kidney Inflammation.” Veterinary Medicine and Science 11, no. 6: e70620. 10.1002/vms3.70620

Funding: The authors received no specific funding for this work.

Data Availability Statement

All the data has been included in the manuscript.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Figure S1: Inflammatory status of control goat kidney. Immunohistochemistry. (A) Absence of CD3‐immunolabeled T cells in the glomerulus of control kidneys. (B) Absence of CD20‐immunolabeled B cells in the glomerulus of control kidneys. (C) Absence of IBA1‐immunolabeled macrophages in the glomerulus of control kidneys. (D) Absence of CD3‐immunolabeled T cells in the tubulointerstitium of control kidneys. (E) Absence of CD20‐immunolabeled B cells in the tubulointerstitium of control kidneys. (F) Absence of IBA1‐immunolabeled macrophages in the tubulointerstitium of control kidneys.

VMS3-11-e70620-s001.jpg (512.1KB, jpg)

Data Availability Statement

All the data has been included in the manuscript.

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