Immunopathology and Immune System Mechanisms in Chronic Disease

Two decades of clinical experience with the immunomodulatory treatment of multiple sclerosis points to distinct immunological pathways that drive disease relapses and progression. Multiple sclerosis is associated with more than 100 different genetic variants that promote disease predisposition and with environmental influences that alter disease penetrance and stochastic occurrences, although the exact triggering events may vary from one patient to the next. Although the immunomodulatory drugs reduce the frequency of relapses, the trade-off of efficacy is a range of side effects, and the long-standing drugs approved for multiple sclerosis do not ultimately halt neurodegeneration.

Multiple Sclerosis and CNS Dysregulation

Dissecting the distinct roles of the immune system in multiple sclerosis is complicated by one, the multicellular pathophysiology that involves infiltrating adaptive and innate immune cells, as well as central nervous system (CNS)-resident innate cells with inflammatory capacity; and two, the chronic nature of the disease that unfolds over a period of many decades. Dysregulation of immune effector–suppressor cell interactions occurs in multiple sclerosis, ultimately resulting in autoreactive adaptive immune cells that are capable of infiltrating and promoting damage within the CNS. However, these cells may not be the main drivers of more chronic, progressive neurodegeneration. Chronic inflammation in multiple sclerosis may reflect a long-term stress response to homeostatic dysregulation in the CNS by tissue-resident innate cells that exceedingly burdens the system, leading to progressive and irreversible neurodegenerative decline.

Macrophages and Tumor Immunity

Regarding cellular mechanisms in other contexts, macrophages are critical mediators of tissue homeostasis, with tumours distorting this proclivity to stimulate proliferation, angiogenesis and metastasis. Tumour macrophages display an ability to suppress T cell recruitment and function as well as to regulate other aspects of tumour immunity. Much of the observed efficacy in targeting these pathways can be traced to the suppressive capacity of macrophages, driven by microenvironmental cues such as hypoxia and fibrosis.

Cardioimmunology: Cardiac Homeostasis and Disease

The past few decades have generated growing recognition that the immune system makes an important contribution to cardiac development, composition and function. Immune cells infiltrate the heart at gestation and remain in the myocardium, where they participate in essential housekeeping functions throughout life. After myocardial infarction or in response to infection, large numbers of immune cells are recruited to the heart to remove dying tissue, scavenge pathogens and promote healing. Under some circumstances, however, immune cells can cause irreversible damage, contributing to heart failure.

Comparison of Immune System Roles

• Multiple Sclerosis: Involves autoreactive adaptive immune cells and CNS-resident innate cells leading to neurodegenerative decline.
• Tumor Immunity: Macrophages suppress T cell function and promote angiogenesis and metastasis.
• Cardioimmunology: Immune cells manage housekeeping and healing but can contribute to heart failure under stress.

Future Perspectives in Immunotherapy

Cancer immunotherapy can successfully promote long-term anticancer immune responses, although there is still only a limited number of patients who benefit from such treatment, and it can sometimes have severe treatment-associated adverse events. Compared with systemic immunomodulation, local immunomodulation may enable more effective treatment at lower doses and, at the same time, prevent systemic toxicity. Local delivery of engineered three-dimensional scaffolds may fulfil this role by acting as synthetic immune niches that boost anticancer immunity. Ultimately, the most imminent goal for future treatment is the concomitant improved targeting of relapses and progression, potentially through combinatorial therapies that modulate both arms of the disease.