Autoimmune disease rarely plays out in a single cell type. Dysregulated immune responses can affect specific tissues and are shaped by the cellular microenvironment around them. Understanding these processes may therefore require looking beyond immune cells in isolation and considering how immune and tissue-specific cells interact.
As interest in human-relevant and non-animal approaches continues to grow, human primary cells offer a controlled way to investigate these responses in a human context. In this article, we look at how these models can help you represent immune–tissue interactions more meaningfully, account for donor and HLA context where relevant, and select readouts that fit your research question.
What are New Approach Methodologies (NAMs)?
New Approach Methodologies (NAMs) encompass a range of innovative approaches used to improve the human relevance of biomedical research and drug development. They include in vitro human-based systems, in silico models, and other emerging platforms.1
Their role in drug development is receiving increasing regulatory attention. FDA draft guidance issued in March 2026, for example, outlines considerations for the validation and use of NAMs in this context. Depending on their intended use, NAMs may complement, reduce, or replace certain animal studies, but they are not a universal substitute for all animal-based research. Human primary cell models can contribute to this broader landscape of human-relevant in vitro approaches.
Why use human primary cells in autoimmune research?
Human primary cells allow you to study autoimmune mechanisms and functional responses in a human cellular context. They can also reduce some of the species-specific differences associated with animal models, as signaling pathways, receptor biology, and immune responses can differ between species.2
Within autoimmune research, this can provide2-5:
- Human cellular context, including human gene expression and signaling.
- Tissue relevance, as tissue-specific primary cells reflect the cell types affected by disease.
- Immune function insight, because primary immune cells support studies of activation, inflammatory signaling, and treatment response.
- Biological relevance, as cells from different donors can help reveal inter-individual differences in biological responses.
However, primary cells also come with practical challenges. Donor-to-donor variability can complicate comparisons, expansion capacity is limited, and specific donor types may be difficult to source.6 Primary cell studies typically also require more planning and experimental control than those using established cell lines.
For a more detailed comparison of the characteristics of primary cells and cell lines, see our infographic on how to choose between primary cells and cell lines for your research.
Which cells are used to model autoimmune diseases?
Several cell types can be used to investigate different aspects of autoimmune disease. The right model depends on the biological question, including whether the focus is on immune-cell behavior, tissue responses, or interactions between the two.3
Common cell types used in autoimmune disease research include primary immune cells such as peripheral blood mononuclear cells (PBMCs), T cells, monocytes, macrophages, and dendritic cells, as well as tissue-specific cells from affected organs.7
Figure 1. From immune responses to tissue effects.
Human primary-cell models in autoimmune research can combine immune cells with tissue-specific primary cells to investigate how immune responses affect local tissue behavior and function. Depending on the research question, these models can support studies of inflammation, tissue injury, barrier changes, fibrosis, and treatment response.
How immune cells capture different aspects of autoimmune responses
Different immune cell populations can provide insight into different aspects of autoimmune biology3,8:
- PBMCs: Broader studies of peripheral immune-cell responses.
- T cells: T-cell activation and antigen-specific activation or autoreactive responses.
- Monocytes and macrophages: Innate immune activity and inflammatory signaling.
- Dendritic cells: Antigen presentation and immune-cell activation.3,9
Typical readouts include cytokine and chemokine production, activation marker expression, proliferation, and differentiation.
How tissue-specific primary cells add the local disease context
In autoimmune disease, non-immune cells in the affected tissue can participate in or respond to ongoing inflammation, and this can influence the trajectory of the disease.10 Depending on the disease and research question, relevant tissue-specific cells may include keratinocytes, fibroblasts, endothelial cells, renal cells, pulmonary cells, and other cell types from the affected organ.
Recent research in rheumatoid and other autoimmune arthritic diseases highlights why this tissue context matters. A 2026 study identified distinct regulatory T-cell states enriched in inflamed synovial tissue rather than blood and showed that local macrophages and fibroblasts helped shape their functional state.11
Immune cell states observed in circulation do not always reflect what is happening within affected tissues. Human primary immune and tissue-specific cells allow you to investigate these cell-cell interactions in a controlled setting and determine how local tissue environments shape inflammatory responses.
Why combine immune cells with tissue-specific primary cells?
Combining immune cells with tissue-specific primary cells allows you to study the bidirectional crosstalk between immune responses and affected tissues. Immune cells can alter tissue-cell behavior, while tissue cells can amplify or regulate inflammatory responses.10
Depending on the research question, these interactions can be investigated using:
- direct or indirect co-culture
- conditioned-medium experiments
- cytokine-stimulated tissue cells
- migration assays
- cytotoxicity assays
Recent rheumatoid arthritis research illustrates the value of this approach. In a 2026 study, researchers co-cultured human PBMCs with fibroblast-like synoviocytes from rheumatoid arthritis patients to investigate immune cell responses in a disease-relevant synovial environment.12
Not every autoimmune study needs a multicellular model. If immune–tissue crosstalk is central to your research question, however, combining relevant human cell types can reveal inflammatory and tissue responses that a single-cell-type model cannot directly capture.
Can primary cells be used for autoimmune drug screening?
Yes, human primary cells can be used in autoimmune drug screening and functional assays to assess how potential treatments affect immune and tissue-cell responses. Depending on the research question, relevant readouts may include13,14:
- inflammatory signaling and cytokine production
- immune-cell activation
- cytotoxicity or tissue-cell survival
- barrier or tissue function
- fibrotic responses
You should select assay readouts based on the mechanism you want to measure. Human primary cell models support the evaluation of diverse therapeutic approaches, including small molecules, biologics, and emerging cell-based therapies.15,16
How should donor variability be handled in autoimmune research?
Donor variability is both a challenge to experimental standardization and a source of biologically relevant information in human primary-cell research.17,18
The key is to decide whether your study should minimize variability or capture it.
When designing a study, consider:
- Number of donors: Use independent donors when the aim is to assess inter-individual variability. Replicates from the same donor do not capture donor-to-donor variability.
- Donor type: Decide whether healthy donors, disease-relevant donors, or both best address the research question.
- Donor characteristics: Consider factors such as age, sex, disease status, or other relevant characteristics where these could influence the response.
- Matched cells: Where interactions between different cell types are being studied, cells from the same donor may help control for differences in genetic background.
Rather than treating donor variability only as experimental noise, you can incorporate it into the study design when human biological diversity is relevant to the question.17,18
When does HLA type matter in autoimmune research?
Human leukocyte antigen (HLA) type matters most when antigen presentation or HLA-restricted immune responses are central to the research question.17,19
This can include:
- autoreactive T-cell responses
- disease-associated HLA alleles
- antigen-presentation assays
- HLA-restricted mechanisms or targets
- donor stratification
- matched or intentionally mismatched immune-cell systems
Not every autoimmune model requires HLA-typed cells. For general inflammatory or functional assays, HLA may not be a defining experimental variable.
For studies where HLA context is important, HLA-typed human primary cells can provide donor-defined material for investigating immune interactions and response patterns. See also our article on HLA in research for more insights on this topic.
What makes an autoimmune model physiologically relevant?
A physiologically relevant autoimmune model captures the human biological context required to answer the specific research question, which is not necessarily the most complex model possible.
Before setting up an autoimmune model, consider the following:
- Biological mechanism: What immune or tissue response needs to be represented?
- Cellular context: Which immune cells and, where relevant, tissue-specific cells are involved?
- Donor context: Could donor characteristics or donor-to-donor variability influence the response?
- HLA requirements: Is HLA relevant to the mechanism being studied?
- Functional readout: Which measurable response will show whether the biological effect has occurred?
The table below summarizes how you can use different cellular models to answer different autoimmune research questions3:
| Research focus | Possible cellular components | Donor / HLA considerations | Example readouts |
|---|---|---|---|
| Immune activation | Relevant primary immune cells | Multiple donors may help assess inter-individual responses | Cytokines, activation markers, proliferation |
| Tissue response to inflammation | Tissue-specific primary cells | Donor characteristics may influence tissue responses | Inflammatory signaling, tissue function, cell injury |
| Immune–tissue interactions | Immune + tissue-specific cells | Matched donor cells may be useful where relevant | Crosstalk, migration, tissue injury or protection |
| Antigen-specific responses | Immune and/or antigen-presenting cells | HLA may be an important experimental variable | Antigen presentation, T-cell activation, cytokine responses |
| Treatment response | Model depends on the therapeutic mechanism | Multiple donors may reveal response variability | Changes in inflammation, cytotoxicity or tissue function |
Table 1. Examples of cellular components and experimental considerations for different autoimmune research questions.
The goal is not to build the most elaborate model possible, but to include the cellular and donor context needed to answer your specific question.
Explore human primary cells for autoimmune research
Autoimmunity can involve various immune cells and affected tissues. Human primary cells can help you study the mechanisms underlying autoimmune disease and the interactions between the different cell types involved in a controlled, human-relevant setting. Explore our blood and immune cell portfolio and immunology research area to find human cell types and donor options that fit your experiments.
Looking for the right cells for your autoimmune model? Whether you're studying immune activation, tissue inflammation, or immune-tissue crosstalk, selecting the right human primary cells is critical. Explore our portfolio of blood, immune, and tissue-specific primary cells to build physiologically relevant autoimmune disease models.
Frequently asked questions
References
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- Overview of autoinflammatory disease cellular models. Accessed August 23, 2026. https://www.creative-bioarray.com/support/overview-of-autoinflammatory-disease-cellular-models.htm
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- Sisto M, Lisi S. Immune and non-immune inflammatory cells involved in autoimmune fibrosis: new discoveries. J Clin Med. 2023;12(11):3801. doi:10.3390/jcm12113801
- Koh B, Gal Oz ST, Sato R, et al. Functional and dysfunctional T regulatory cell states in human tissues in RA and other autoimmune arthritic diseases. Nat Immunol. 2026;27(7):1449-1461. doi:10.1038/s41590-026-02540-4
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- Gibson D, Leonforte C, Madrigal A. Strategies for dealing with donor variability. Cell Gene Ther Insights. Published online 2018. doi:10.18609/cgti.2018.087
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