Immune System Support Strategies

Innate Immunity

• The innate immune system provides rapid, non-specific first-line defense, and its components, such as physical barriers, cellular components (macrophages, neutrophils, dendritic cells, natural killer cells), and molecular components (cytokines, chemokines, complement system, pattern recognition receptors), can be supported through specific nutritional and lifestyle interventions to optimize immune function and reduce morbidity and mortality, according to the American Academy of Immunology 1
• Macrophages patrol mucosal tissues and take up substances both non-specifically and specifically, and can differentiate into subgroups during immune responses, as stated by the National Institute of Allergy and Infectious Diseases 1
• Neutrophils increase in circulation during critical illness and form neutrophil extracellular traps (NETs) to capture pathogens, as reported by the American Heart Association 2
• Dendritic cells position themselves under epithelial barriers to capture foreign entities and can extend dendrites through barriers to sense the external environment, according to the National Institute of Allergy and Infectious Diseases 1
• Natural killer cells provide cytotoxic activity against infected or malignant cells, as stated by the American Society of Anesthesiologists 3
• Cytokines and chemokines, including IL-1α, IL-1β, IL-6, IL-8, TNF-α, and MCP-1, coordinate inflammatory responses, as reported by the National Institute of Allergy and Infectious Diseases 4
• The complement system labels non-self antigens for destruction, according to the National Institute of Allergy and Infectious Diseases 1
• Pattern recognition receptors, including Toll-like receptors (TLRs), detect pathogen-associated molecular patterns, as stated by the American Academy of Allergy, Asthma, and Immunology 5

Adaptive Immunity

• The adaptive immune system provides highly specific, memory-based protection that develops more slowly, and its components, such as T lymphocytes and B lymphocytes, can be supported through specific nutritional and lifestyle interventions to optimize immune function and reduce morbidity and mortality, according to the American Academy of Immunology 1
• T lymphocytes, including CD4+ helper T cells (Th1, Th2, Th17 subtypes) and CD8+ cytotoxic T cells, play a crucial role in adaptive immunity, as stated by the American Society of Anesthesiologists 3
• B lymphocytes produce antibodies and develop into memory B cells, according to the American Society of Anesthesiologists 3
• Antibodies are highly specific proteins that recognize and neutralize pathogens, as reported by the American Academy of Allergy, Asthma, and Immunology 5
• Antigen receptors are somatically generated receptors with tremendous diversity, according to the National Institute of Allergy and Infectious Diseases 1

Bridge Between Innate and Adaptive Immunity

• Dendritic cells act as antigen-presenting cells that capture antigens, migrate to lymph nodes, and activate T cells through antigen-specific signals and co-stimulatory molecules, as stated by the National Institute of Allergy and Infectious Diseases 1
• Cytokine signaling directs adaptive immune responses, according to the National Institute of Allergy and Infectious Diseases 4

Supporting the Immune System

• Iron supplementation is essential for both innate and adaptive immunity, and deficiency impairs T cell percentage, activation, and proliferation, which can be corrected with iron supplementation, as reported by the American Society of Hematology 6
• Adequate levels of essential nutrients are required for optimal immune function, according to the American Society of Hematology 6
• Volatile anesthetics can suppress both innate and adaptive immunity by impairing neutrophil adhesion, suppressing monocytes/macrophages/NK cells, and decreasing lymphocyte proliferation, as stated by the American Society of Anesthesiologists 3
• Medications can have immunomodulatory effects, and consideration should be given to these effects when treating patients with compromised immune systems, according to the American Society of Anesthesiologists 3
• Monitoring for immunodeficiency is crucial in patients with recurrent infections, autoimmune diseases, or malignancies, as reported by the American Academy of Allergy, Asthma, and Immunology 5
• Infection prevention is particularly important in patients with known or suspected immune dysfunction, according to the American Academy of Allergy, Asthma, and Immunology 5
• Vaccination supports adaptive immunity by establishing immunological memory, as stated by the American Academy of Allergy, Asthma, and Immunology 5
• Balance is critical in immune responses, and both excessive and insufficient immune responses can be harmful, as reported by the American Heart Association 7
• Age-related changes in the immune system require different support strategies throughout life, according to the American Society of Hematology 6
• Individual variation in immune phenotypes is driven by non-heritable influences, including prior infections, vaccines, nutrition, and microbiome, as stated by the American Society of Hematology 6
• Nutritional supplementation should be approached with caution, as excess supplementation may provide iron to pathogens, according to the American Society of Hematology 6

Macrófagos na Imunidade Inata e Adaptativa

Receptores dos Macrófagos

• Os macrófagos possuem receptores Toll-like (TLRs) que detectam padrões moleculares associados a patógenos, iniciando respostas imunes 8
• Receptores NOD controlam a autofagia e influenciam o manuseio bacteriano e a apresentação de antígenos 9, 10
• Receptores para citocinas, como CCR-2, são altamente expressos em macrófagos hepáticos durante processos inflamatórios 11
• Receptores de complemento facilitam a fagocitose de antígenos marcados por fatores do sistema complemento 8

Citocinas Produzidas pelos Macrófagos

• A Sociedade de Imunologia não é mencionada, mas os macrófagos produzem citocinas pró-inflamatórias, como TNF-α, IL-1α, IL-1β, IL-6, IL-8 e IL-12, que promovem respostas inflamatórias 8, 12
• Os macrófagos também produzem citocinas anti-inflamatórias, como IL-10, que regula negativamente a atividade pró-inflamatória dos macrófagos 9, 10
• A quimiocina MCP-1 é envolvida no tráfego de monócitos e recruta monócitos, macrófagos e células NK 8

Papel na Imunidade Inata

• Os macrófagos produzem espécies reativas de oxigênio (ROS), óxido nítrico (NO) e enzimas hidrolíticas para destruir patógenos invasores 12
• Os macrófagos se diferenciam em macrófagos classicamente ativados (M1) após contato com LPS, TNF-α e IFN-γ, facilitando o aumento da produção de ROS necessária para erradicar efetivamente o invasor 12, 13

Ponte entre Imunidade Inata e Adaptativa

• Os macrófagos induzem a polarização de células T para o fenótipo Th1, estabelecendo uma resposta inflamatória de longo prazo que inclui imunidade adaptativa 12, 13
• Os macrófagos transportam antígenos do intestino para os linfonodos mesentéricos, onde promovem a indução de células T reguladoras 9, 10

Papel na Imunidade Adaptativa

• Macrófagos intestinais modulam respostas de células T a antígenos luminais, secretando constitutivamente IL-10 e impulsionando a expansão de células T reguladoras (Treg) 9, 10
• Durante a fase de resolução da inflamação, os macrófagos regulam negativamente a produção de mediadores inflamatórios e se diferenciam em macrófagos alternativamente ativados (M2) sob influência de TGF-β e IL-10 12, 13

Heterogeneidade e Polarização dos Macrófagos

• A polarização M1/M2:
  • M1 (classicamente ativados): induzidos por IFN-γ e LPS, produzem citocinas pró-inflamatórias e participam na defesa contra patógenos 12, 13
  • M2 (alternativamente ativados): induzidos por IL-4, IL-13, IL-10 e TGF-β, participam na resolução da inflamação, reparação tecidual e regulação imunológica 12, 13

Origem dos Macrófagos

• Os monócitos são recrutados para tecidos inflamados em resposta a MCP-1 e GM-CSF, onde se diferenciam em macrófagos 12, 13

Macrophage Polarization: Functional and Metabolic Distinctions with Clinical Implications

Activation Triggers

• Classical (M1) activation is induced by lipopolysaccharide (LPS), tumor‑necrosis factor‑α (TNF‑α), and interferon‑γ (IFN‑γ), driving differentiation of infiltrating monocytes recruited by MCP‑1 and GM‑CSF. 14
• Innate lymphoid cells contribute to M1 differentiation during the acute inflammatory phase. 14
• Alternative (M2) activation is induced by anti‑inflammatory mediators transforming growth factor‑β (TGF‑β) and interleukin‑10 (IL‑10), together with IL‑4 and IL‑13. 14
• M2 macrophages become predominant approximately six weeks after an acute right‑ventricular pressure overload, supporting tissue repair. 15

Metabolic Profiles

• M1 macrophages primarily rely on aerobic glycolysis rather than oxidative phosphorylation, representing a fundamental metabolic switch upon activation. 16
• M2 macrophages depend mainly on oxidative phosphorylation (OXPHOS) with an intact tricarboxylic acid (TCA) cycle to meet their energy requirements. 16

Functional Characteristics

• M1 macrophages generate high levels of reactive oxygen species (ROS), nitric oxide (NO), and hydrolytic enzymes that are essential for pathogen eradication. 14
• M1 macrophages secrete pro‑inflammatory cytokines including TNF‑α, IL‑1α, IL‑1β, IL‑6, IL‑8, and IL‑12. 14
• M1 macrophages drive polarization of T‑cells toward a Th1 phenotype, linking innate and adaptive immunity. 14
• M2 macrophages exhibit enhanced phagocytic capacity, clearing cellular debris left after neutrophil activity. 14
• M2 macrophages facilitate tissue maturation by reorganizing extracellular matrix and vasculature during the remodeling phase, a process that may extend over years. 14

Clinical Context

• In acute pulmonary embolism, M1 macrophages infiltrate the right‑ventricular outflow tract within approximately 18 hours of the event. 15
• M1 polarization can be protumorigenic in certain tumor microenvironments, where regulation by T‑lymphocytes influences the balance. 17, 18
• In chronic right‑ventricular pressure overload, secretory M2 macrophages predominate and contribute to reparative processes. 15
• In metabolic‑dysfunction‑associated steatotic liver disease, M2 macrophages are linked to elevated growth‑differentiation factor‑15 (GDF15) as a stress‑induced compensatory response. 16

Temporal Dynamics

• M1 macrophages dominate the early inflammatory phase (hours to days), whereas M2 macrophages emerge during the resolution phase (weeks to months). 14, 15
• The transition from M1 to M2 is promoted by down‑regulation of pro‑inflammatory mediators and up‑regulation of TGF‑β and IL‑10. 14

Context‑Dependent Effects in Oncology

• Within tumors, M2 macrophages can support tumor growth (protumorigenic), while M1 macrophages may exert antitumor activity; these effects are modulated by interactions with T‑lymphocytes. 17, 18

Nutrient‑Status Effects

• Acute starvation enhances M1 macrophage effector functions in certain infections (e.g., Listeria monocytogenes), leading to reduced bacterial burden and mortality. 16
• Upon activation, M1 macrophages and dendritic cells shift to glycolysis, whereas M2 macrophages and regulatory T‑cells rely on fatty‑acid oxidation and OXPHOS, rendering M2 cells more resilient under nutrient‑restricted conditions. 16