Immunology of stress: A review article
Open accessAbstract
Stress significantly impacts the immune system, affecting susceptibility to illness and overall health. This review examines the intricate relationship between stress and the immune system, offering insights having practical implications for health and disease prevention. Stress can significantly trigger molecular and immune modulation, affecting the distribution and trafficking of immune cells in various organs and altering their composition in the blood. The review delves into two key pathways connecting stress and immunity: the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic nervous system. Stress activates the neuroendocrine system and triggers microglia in the brain, releasing stress hormones and neurotransmitters that modulate the function and movement of immune cells. Acute stress can temporarily strengthen immunity and promote protection during infection; in contrast, chronic stress dysregulates or inhibits immune functions. Chronic stress causes an increase in cortisol levels through the HPA axis, ultimately suppressing the immune response. Recognizing stress triggers and implementing effective stress management techniques can significantly impact individuals’ well-being. This review indicates that immune cells express genes differentially in response to stress, suggesting individual variabilities in the immune response against stress. This underscores the need for a personalized approach to stress management. This review also highlights the potential link between chronic stress and autoimmune disorders and warrants further investigation.
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Chronic psychological or physiological stress can exacerbate RA through neuro-immune-bone axis pathways.
“Recent studies indicate that chronic psychological or physiological stress can exacerbate RA through neuro–immune–bone axis pathways [76]”
From Interorgan Communications in Skeletal Pathophysiology: From Molecular Pathways to Multidisciplinary Therapies (2026) · cites this paper as [76]
Section 7, “Chronic Stress and Immune Dysregulation” (page unavailable), reports that patients with rheumatoid arthritis who have elevated stress levels report greater disease activity and more frequent flare-ups. Sections 4 and 8 describe stress-related neural and immune mechanisms, but the copy does not connect RA exacerbation specifically to a neuro–immune–bone axis pathway. (LLM, conf=0.86)
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“At feedlot entry, the acute phase response primes the body to defend against potential injury or infection [54].”
Makyeyeva, L., Belenichev, I. F., Aliyeva, O. G., Frolov, O., Petakh, P., & Kamyshnyi, O. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1656214 · Cited by 4 · see citing works
“Emerging evidence highlights the systemic interplay between chronic stress, immune dysregulation, and metabolic disturbances mediated by transcriptional and microbial mechanisms (133, 134).”
Pedrinelli, V., Rimoldi, B., Conti, L., Bordacchini, A., Parrini, L., Betti, L., Giannaccini, G., Dell’Oste, V., & Carmassi, C. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262411835 · Cited by 4 · see citing works
“Allostasis processes involve sympathetic and neuroendocrine branches intertwined with the activity of the immune system [27–32].”
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“66,67 72–76 Histological evidence of lipid droplet depletion suggests localized lipolytic imbalance, which may compromise acinar cell integrity.”
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“60–65 Metyrapone partially restored immune-gene expression, aligning with glucocorticoid receptor– dependent modulation of immune rhythmicity via known interactions between the core clock machinery (e.g., BMAL1 ) and inflammatory regulators such as NF-κ B. 56 Disruption of immune circadian rhythms…”
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“This, in turn, accelerates the aging process (De La Fuente, 2008) by contributing to chronic anxiety and stress, and various diseases, including metabolic disorders (Alotiby, 2024).”
Alhamawi, R. M., Halawani, F. A., Hakeem, S. F., Alslimi, H. A., Alhamawi, E. M., Aljohani, A. M., Mohammed, I., Zahid, H., & Almutawif, Y. A. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1698155 · Cited by 3 · see citing works
“Cortisol is a glucocorticoid hormone produced by the adrenal cortex, which is known as an immunosuppressive agent (38).”
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Konflik Bioetika dalam Fenomena Adu Ayam: Analisis Kesejahteraan Hewan dan Nilai Etik Lokal
Rohim, R., Musthofa, M. H., Noerdin, I., & Cahyanto, T. (2025) · Switch Jurnal Sains dan Teknologi Informasi · doi:10.62951/switch.v3i6.715 · Cited by 3 · see citing works
Nutritional modulation of biochemical pathways in stress response: A comprehensive review
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Redefining surgical oncology: active immune microenvironment modulation beyond tumor resection
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The impact of urban stress factors on mental health: a review of foreign studies
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Alotiby, A. A. (2025) · Cureus · doi:10.7759/cureus.77317 · Cited by 3 · see citing works
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Nechita, P., Oroian, B. A., MD, P. S., Schipor, P. D., Enache, A.-L., & Popa, M. V. (2025) · Bulletin of Integrative Psychiatry · doi:10.36219/bpi.2025.2.02 · Cited by 3 · see citing works
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“Chronic stress, commonly seen in individuals with depression and PTSD, elevates cortisol levels, which in turn suppresses immune function and compromises the body’s ability to resist infections [51, 52].”
Kim, G.-H., Lee, K., Choi, H.-S., Han, J. S., & Kim, S. (2025) · Animals · doi:10.3390/ani15060889 · Cited by 3 · see citing works
“Prolonged exposure to elevated cortisol levels due to chronic stress can impair immune function and exacerbate inflammation, contributing to various diseases, such as chronic obstructive pulmonary disease, inflammatory bowel disease, and metabolic disorders [3–5].”
RetractedRisk Factors for Chronic Pain in Women: The Role of Violence Exposure in a Case–Control Study
Uvelli, A., Pugliese, E., & Ferretti, F. (2025) · Life · doi:10.3390/life15060976 · Cited by 3 · see citing works
Schmitt, A., Andrews, N., Yasuda, K., Hodge, M., & Ryznar, R. J. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26093945 · Cited by 2 · see citing works
“However, chronic and traumatic stress can lead to the dysregulation of the HPA axis through glucocorticoid resistance [6,7], and shift the immune response into a chronic state of inflammation [8–10].”
Assessment of the adaptogenic properties of herbal tea based on pine needles and microstrobiles
Zhamsaranova, S. D., Ширеторова, В. Г., Аркадьевна, Э. С., Тыхеев, А. А., & Лебедева, С. Н. (2025) · Food systems · doi:10.21323/2618-9771-2025-8-1-124-133 · Cited by 2 · see citing works
Enhancing Survival Following High-Risk Surgery by Modulating Actionable Items within the Pathobiome
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Hematological Changes and Immunomodulation of Neutrophil and Monocyte Populations in Shelter Dogs
Kulka, M., Szopa, I. M., & Klockiewicz, M. (2025) · Animals · doi:10.3390/ani15131988 · Cited by 2 · see citing works
“Numerous studies have shown that stress modifies the production of inflammatory cytokines and modulates the immune responses [5,6].”
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“Cortisol, an endogenously secreted glucocorticoid, is involved in stress responses, immune modulation, and metabolic balance [19].”
Mapping genomic regions affecting resilience traits in a large dairy farm of Holstein cows
Punturiero, C., Delledonne, A., Ferrari, C., Bagnato, A., & Strillacci, M. G. (2025) · Frontiers in Animal Science · doi:10.3389/fanim.2025.1627086 · Cited by 2 · see citing works
Impact of physical and psychological stressors on tumor growth and immune responses in breast cancer
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Krefting, F., Hölsken, S., Sondermann, W., & Schedlowski, M. (2025) · Clinical Immunology · doi:10.1016/j.clim.2025.110611 · Cited by 2 · see citing works
Hagström, D., Sundström, A. E., Hakelind, C., Nordin, S., & Nordin, M. (2025) · Stress and Health · doi:10.1002/smi.70119 · Cited by 2 · see citing works
“…possible explanation for the fact that anxious tension and gastrointestinal problems were the strongest predictors of burnout is that both stress (Alotiby 2024) and gastrointestinal problems (Layunta et al. 2024) are associated with the immune response and a suppressed immune response is…”
Research Hotspots and Emerging Trends of Schizophrenia and Immune Response: A Bibliometric Analysis
Zhang, Y. (2025) · Brain and Behavior · doi:10.1002/brb3.71054 · Cited by 2 · see citing works
“Lastly, the interplay between stress and neuroinflammation represents an increasingly important area of research, as environmental stressors are known to activate inflammatory pathways, exacerbate oxidative stress, and worsen clinical outcomes in schizophrenia (Alotiby 2024; Ravi et al. 2021).”
Comparative Characterization of High-Grade Glioma Models in Rats: Its Importance for Neurobiology
Kudelkina, V. V., Bulava, A., Gorkin, A. G., Venerina, Y. A., & Alexandrov, Y. I. (2025) · Clinical and Translational Neuroscience · doi:10.3390/ctn9040058 · Cited by 2 · see citing works
Mazon, C., Betters, R. K., Salmeron-Ceballos, G., Tomaziefski, A., Coffman, C. N., Simonson, R., & Tunc‐Ozcan, E. (2026) · IBRO Neuroscience Reports · doi:10.1016/j.ibneur.2026.01.003 · Cited by 2 · see citing works
“Stress further amplifies these sex-specific responses by increasing microglial reactivity (Schramm & Waisman, 2022) and elevating pro-inflammatory cytokine production (Alotiby, 2024), which in turn can alter synaptic remodeling, neurotransmitter dynamics, and circuit excitability.”
Targeting immunometabolism in cancer through pharmacological and lifestyle interventions
Tan, R. J. Y., Liu, Y., Chen, W., Liang, Y., & Ling, G. S. (2026) · PLoS Biology · doi:10.1371/journal.pbio.3003617 · Cited by 2 · see citing works
“Indeed, it is known that low glucose availability triggers the secretion of cortisol via the HPA axis as a stress response mechanism [114], and that elevated cortisol correlates with poor immune activation and function [115].”
Dera, A. A., Alqahtani, L. M., & Alghamdi, A. (2025) · King Khalid University journal of health sciences. · doi:10.4103/kkujhs.kkujhs_18_25 · Cited by 2 · see citing works
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El‐Raghi, A. A., Fawzy, M. S., Elmorsy, E. M., Doghaither, H. A. A., Al-Ghafari, A. B., Hassan, M. S., Gad, A. M. A., Abourashed, N. M., & Abdelhady, D. (2026) · Italian Journal of Animal Science · doi:10.1080/1828051x.2026.2639681 · Cited by 2 · see citing works
Circadian misalignment in PCOS: role of sleep and light
Samaddar, S., Ghosh, S., Kumar, A., Yadav, P., Yadav, M., & Dahiya, R. (2026) · Biological Rhythm Research · doi:10.1080/09291016.2026.2651558 · Cited by 2 · see citing works
“Its effect on immune function and mood control should be considered seriously, and supplementation should be closely monitored to avoid any adverse effects (Alotiby 2024).”
Zheng, M., Sun, S., & Lv, B. (2026) · Journal of International Medical Research · doi:10.1177/03000605261447130 · Cited by 2 · see citing works
“13,14 The pathogenesis of IBS involves multiple interrelated mechanisms, with key contributing factors including visceral hypersensitivity, low-grade inflammation, impaired intestinal barrier function, gastro-intestinal motility disorders, psychological disturbances, brain–gut axis (BGA)…”
Domestic Violence Law and Maqāṣid al-Syarī’ah in Protecting Families from Psychological Violence
Nasyiah, I., Nasrulloh, M., Humairoh, Z., Fakhruddin, F., & Saidon, R. (2026) · Unnes Law Journal · doi:10.15294/ulj.v12i1.48249 · Cited by 2 · see citing works
Valiente-Gómez, A., Bücker, J., Fontana-McNally, M., Gatto, D. L., Guinart, D., Moreno‐Alcázar, A., Rodriguez, C. C., Gil, C. D. C., Padberg, F., Pardina-Torner, H., et al. (2026) · EClinicalMedicine · doi:10.1016/j.eclinm.2026.103987 · Cited by 2 · see citing works
Zhou, H., Wang, X., & Sha, S. (2026) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2026.1829622 · Cited by 2 · see citing works
“…promoting inflammatory factors, activating natural killer cells and macrophages, and recruiting white blood cells via corticosterone and adrenaline (Alotiby, 2004), whereas chronic stress impairs immune function, inhibits lymphocyte proliferation, disrupts cytokine balance, and, through prolonged…”
Nys, L. D. (2026) · Journal of Geriatric Oncology · doi:10.1016/j.jgo.2026.102854 · Cited by 2 · see citing works
Gan, D., Qin, L., & Xiao, G. (2026) · Research · doi:10.34133/research.1319 · Cited by 1 · see citing works
“Recent studies indicate that chronic psychological or physiological stress can exacerbate RA through neuro–immune– bone axis pathways [ 76 ].”
Andong, F. A., Okoye, K. C., Nnachi, I. A., Attamah, G. N., Odo, U. U., Mayowa, E. S., Agina, O. A., Ekere, S. O., Ngonadi, J. U., Nwanozie, P. O., et al. (2025) · Avian Biology Research · doi:10.1177/17581559251345277 · Cited by 1 · see citing works
Complex war trauma in an adolescent: diagnosis and rehabilitation (clinical case)
Kabantseva, A. V., Панченко, О. А., Tsapro, N. P., & Serdyuk, I. A. (2025) · CHILD`S HEALTH · doi:10.22141/2224-0551.20.6.2025.1897 · Cited by 1 · see citing works
Mishra, S., & Mohanty, B. (2025) · Nutrire · doi:10.1186/s41110-025-00369-9 · Cited by 1 · see citing works
“In our study, LPS enhanced the pro-oxidants (LPx) and decreased the antioxidants (SOD, CAT) levels in immune organs (spleen and thymus) as observed in others [72, 73].”
Chakma, J., Choravada, D. R., & Champati, A. (2025) · Cogent Food & Agriculture · doi:10.1080/23311932.2025.2573872 · Cited by 1 · see citing works
“…2009). these enzymes include superoxide dismutase (sOd), catalase (cAt), and Glutathione Peroxidase (GPx) (ighodaro & Akinloye, 2018; Jomova et al., 2024). the expression of antioxidant enzyme genes is regulated by transcription factors, primarily nrf2 (ngo & duennwald, 2022). under normal…”
Stocker, A., Giangreco, B., Revet, A., Alameda, L., Bui, É., Bürgin, D., Clemens, V., Cortese, S., Schechter, D. S., Schmid, M., et al. (2025) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2025.106393 · Cited by 1 · see citing works
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Botia, M., Muñoz-Prieto, A., Ortín-Bustillo, A., Maslov, D. R., Rubić, I., Fuentes, P., Jiménez-Caparrós, F. J., Hernández-Gómez, J. L., Avellaneda, A., Cerón, J. M. C., et al. (2026) · Animal Welfare · doi:10.1017/awf.2025.10055 · Cited by 1 · see citing works
“This is consistent with evidence that stress induces the release of hormones and neuro-transmitters that modulate the function and movement of immune cells (Alotiby 2024).”
Coulter, J. E. (2026) · The Design Journal · doi:10.1080/14606925.2026.2625752 · Cited by 1 · see citing works
“To adapt to stress the body produces cortisol until the body’s resources have been depleted and it moves to exhaustion stage (McFarlane, 2024). ongoing and un-managed stress significantly impacts the immune system, affecting susceptibility to illness and overall health (Alotiby, 2024).”
Stress as a factor in female reproductive health disorders
Adamyan, L. V., Avetisyan, J. S., Osipova, A. A., Pivazyan, L. G., Mailova, K. S., & Saakyan, S. V. (2026) · Russian Journal of Human Reproduction · doi:10.17116/repro20263201111 · Cited by 1 · see citing works
Mityuryayeva-Kornijko, I. O., Klets, T., Burlaka, I. A., Коротич, Т. І., & Odayskyi, O. M. (2026) · Eastern Ukrainian Medical Journal · doi:10.21272/eumj.2026;14(1);126-137 · Cited by 1 · see citing works
Inorganic biomaterials as immunomodulators: dual strategies for activation and suppression
Si, X., Lu, Y., & Zha, Z. (2026) · Science China Materials · doi:10.1007/s40843-025-4001-x · Cited by 1 · see citing works
ЕКСПЕРИМЕНТАЛЬНЕ ДОСЛІДЖЕННЯ ВПЛИВУ ГОРМОНІВ СТРЕСУ НА НЕСПЕЦИФІЧНУ ПРОТИПУХЛИННУ ІМУННУ ВІДПОВІДЬ
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“…відомо, глюкокортикоїди мають подвійний вплив на імунну відповідь: у коротко-строкові терміни вони посилюють активність імунних клітин (зокрема ПКК та Мф) та сприя-ють виробленню ними прозапальних цитокінів; тривалий вплив призводить до порушення імунної регуляції та розвитку імуносупресії [17–19].”
Risk Factors for Secondary Immunodeficiency in the Aged
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“First, psychological stress, immune-stress responses, motivation, adherence, sleep, behavioral activation, and caregiver or social-support indicators should be recorded, because stress-related immune pathways may influence both recovery capacity and biomarker interpretation (38).”
Papachristodoulou, E., Kakoullis, L., Christophi, C. A., Derk, C. T., Chatzittofis, A., Alexopoulos, P., Καρανικόλας, Μ., Velissaris, D., & Parperis, K. M. (2026) · Rheumatology International · doi:10.1007/s00296-026-06183-4 · Cited by 1 · see citing works
“Chronic psychological stress activates neuroendocrine stress pathways, primarily the hypothalamic-pituitary-adrenal axis (HPA) and the sympathetic nervous system, resulting in alterations in cortisol and catecholamine signaling that influence immune regulation [ 5].”
Babayeva, Z., Babayeva, A., & Miller, A. H. (2026) · Shusha Scientific Journal · doi:10.66366/ssj.2026.66 · Cited by 1 · see citing works
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Russu, E.-A., Popa, L. G., Burcea, A., Bohîlțea, L. C., Bogdan-Andreescu, C. F., Banateanu, A. M., Poalelungi, C.-V., & Albu, C.-C. (2025) · Romanian Journal of Oral Rehabilitation · doi:10.62610/rjor.2025.2.17.51 · Cited by 1 · see citing works
Jaimes, M. S. V., Chaimano, S., Lin, S., Chang, Y., Yang, C.-T., Hsieh, S., Goh, J. O. S., Chu, Y.-W., & Tsai, M. (2025) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2025.107624 · Cited by 1 · see citing works
- Authors
- Alotiby, A.
- Affiliations
- Umm al-Qura University (SA)
- Corresponding author
- Alotiby, Amna
- ORCID
- Alotiby, Amna
- Venue
- Journal of Clinical Medicine
- Publisher
- MDPI AG
- Published
- 2024-10-25
- Volume
- 13
- Issue
- 21
- Pages
- 6394
- ISSN
- 2077-0383 (ISSN-L)
- PMC
- PMC11546738
- OpenAlex
- W4403749058
- Cited by
- 253
- References
- 51
- Citations by year
- 2026: 145 · 2025: 108
- FWCI
- 9.71
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Clinical Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Psychiatry and Mental health › Cancer, Stress, Anesthesia, and Immune Response
- Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
- Keywords
- stress, immune system, hypothalamic-pituitary-adrenal axis, sympathetic nervous system, cortisol, chronic stress, acute stress, immune cell trafficking, neuroendocrine-immune interaction, microglia, stress hormones, stress management, autoimmune disease, immune gene expression
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