Inflammation and Immunology



Inflammation and Immunology


Benjamin F. Ricciardi, MD, FAAOS

Edward M. Schwarz, PhD


Dr. Ricciardi or an immediate family member serves as a paid consultant to or is an employee of DePuy, a Johnson & Johnson Company and has received research or institutional support from Johnson & Johnson. Dr. Schwarz or an immediate family member is a member of a speakers’ bureau or has made paid presentations on behalf of Asahi KASEI Pharma Corporation; serves as a paid consultant to or is an employee of Asahi KASEI Pharma Corporation, DePuy, a Johnson & Johnson Company, Integrated Biotechnology, MedImmune, Musculoskeletal Transplant Foundation, and Regeneron; has stock or stock options held in Parvizi Surgical Innovations, LLC, and Telephus Biosciences; has received research or institutional support from DePuy, a Johnson & Johnson Company, Eli Lilly, and Telephus; and has received nonincome support (such as equipment or services), commercially derived honoraria, or other non-research-related funding (such as paid travel) from Telephus Biosciences.





ABSTRACT

Host responses to trauma, infection, and diseases are central to all orthopaedic injury repairs, and thus a fundamental understanding of the immediate, acute, chronic, and lifelong molecular and cellular mechanisms that govern inflammation and immunology is critical for an understanding of musculoskeletal disease. It is important to be knowledgeable about basic immunology, including innate immune responses driven by proinflammatory cytokines and chemokines from myeloid cells that initiate host defense and tissue repair, and its transition to antigen-specific acquired immunity and lifelong protection against pathogens by lymphocytes. As sustained production of proinflammatory cytokines (tumor necrosis factor, interleukins 1 and 6) leads to chronic inflammation that inhibits tissue repair and promotes immune-mediated inflammatory disorders (such as inflammatory arthritis), new small-molecule drugs and biologics have emerged as standards of care. Additionally, there have been transformative advances in cancer immune checkpoint regulator therapy (programmed cell death protein 1 and programmed cell death ligand 1 inhibitors). As all areas of medicine have been dramatically affected by the COVID-19 pandemic, the cytokine storm, described as a mechanism of severe acute respiratory syndrome, and the fundamentals of active vaccinations (traditional protein antigen, replication-defective DNA viral vectors, and messenger RNA nanoparticles) versus passive immunization (convalescent sera and monoclonal antibodies) are important topics as well as the limitations of immunization approaches, including nonneutralizing antibodies, transient immunity, and breakthrough strains. Inflammation and immunology are two essential translational science disciplines that need to be considered in understanding pathophysiology and mechanisms of many emerging disease-modifying drugs for orthopaedic disorders.

Keywords: active vaccination; biologics; checkpoint inhibition; cytokines; inflammation; innate immunity; passive immunization


Introduction

Trauma and environmental insults to the human body trigger an immediate innate immune response to endogenous and exogenous factors that result in local inflammation proportionate to the noxious stimulus. For effective tissue repair, the acute insult needs to be resolved by phagocytic cells (neutrophils and macrophages) that are recruited into the tissue from the blood. Phagocytic cells are responsible for clearing debris, invading pathogens, and dead (necrotic) and dying (apoptotic) cells. Additionally, these inflammatory cells can further amplify this innate immune response by producing cytokines and chemokines that lead to edema and further tissue catabolism, which is the etiology of chronic musculoskeletal diseases such as rheumatoid arthritis. In the cases of pathogenic challenge
and neoplasia, the phagocytic cells present antigens to helper T cells that orchestrate acquired cellular and humoral immune responses. It is important to discuss the fundamentals of these innate and adaptive immune responses and the molecular and cellular pathways that control them, many of which can be targeted by specific drugs and biologic antagonists. Immunizations work but there are limitations to their effectiveness.


Innate Immunity and Inflammation

All eukaryotic cells are susceptible to infection by viruses and bacteria, and thus have evolved intracellular triggers and responses to defend themselves against pathogens. These intracellular defense mechanisms include the interferon (IFN)-induced double-stranded RNA-dependent protein kinase that shuts down protein synthesis in virus-infected cells,1 xenophagy that mediates degradation of pathogens in membrane-bound compartments, and IFN-regulated guanosine triphosphatases that promote rupture of pathogen-containing vacuoles and microbial degradation.2 Multicellular organisms have the additional burden of protecting their uninfected cells from infected and traumatized cells within a tissue. Hence, they have evolved intercellular mechanisms that rely on soluble proteins (cytokines and chemokines) released from the damaged cells that signal the healthy cells to protect themselves by inducing intracellular immune mechanisms, and recruit activated phagocytes to clear the necrotic and apoptotic cells and invaders. Collectively, these molecular and cellular immediate-response systems are known as innate immunity, which is highly conserved from fruit flies to humans.3

There are two central signaling pathways that are used in innate immunity. The first is the Toll-like receptor (TLR) signaling pathway, in which transmembrane receptors recognize foreign molecules or pathogen-associated molecular patterns (PAMPs),4 which cannot be synthesized by eukaryotic cells (Figure 1). These include flagella and bacterial cell wall components. There also are biochemicals that are released from necrotic host cells that act as TLR ligands. These include DNA and RNA and are referred to as damage-associated molecular patterns (DAMPs). Once TLRs are activated by PAMPs or DAMPs,4,5 they initiate signal transduction through the nuclear factor kappa B pathway, which results in proinflammatory cytokine synthesis within minutes.6 These proinflammatory cytokines, which include IFNs, tumor necrosis factor (TNF), and interleukins (ILs), constitute the second central signaling event during innate immune responses (Figure 2). TNF receptor signaling activates the nuclear factor kappa B cascade, similar to TLR signaling,7 but it also activates apoptosis through its death domain.8 Thus, TNF signaling initiates and amplifies inflammation by inducing the synthesis of other proinflammatory molecules such as IL-1, IL-6, and prostaglandins, and commences the end of inflammation by initiating programmed cell death in all of the inflammatory cells recruited into the tissue. Once all the PAMPs and DAMPs are cleared from the tissue by the inflammatory macrophages (referred to as M1 macrophages), these cells undergo apoptosis and are cleared by scavenger macrophages (referred to as M2 macrophages), and the tissue returns to homeostasis.9


Orthopaedic Disease From Chronic Inflammation

In addition to its critical role in host defense, innate immunity also initiates tissue repair responses, including angiogenesis, recruitment of mesenchymal stem cells, and the induction of growth and differentiation factors (eg, bone morphogenetic proteins).10 However, if proinflammatory cytokine expression persists, so does tissue catabolism, which can lead to musculoskeletal disease (Table 1). Certain chronic inflammatory diseases can be caused by perpetual exposure to PAMPs and DAMPs, such as deep bacterial infections or implant wear debris-induced osteolysis.11 In these cases, cure often requires surgical elimination of the proinflammatory stimulator. There also are genetic mutations that lead to exaggerated innate immune responses, including chronic recurrent multifocal osteomyelitis, which results in tissue damage from sterile inflammation, which can be effectively treated with anti-TNF therapy.12 Unfortunately, there are also immune-mediated inflammatory disorders in which the etiology of the chronic inflammation is unknown (eg, rheumatoid arthritis, multiple sclerosis).13 Although biologic therapies have had a major effect on immune-mediated inflammatory disorder severity and progression, there is no cure, and clinical management of breakthrough flares remains a major challenge.


Biologic Therapies in Orthopaedics

Biologic therapies are defined as treatments that are produced in living organisms, in contrast to herbal extracts and chemically synthesized small molecules. Another distinction is that biologics are primarily protein in nature and must be injected or infused into patients to bypass the digestive system.14 Mechanistically, biologics either act as ligands to a host cell surface receptor

(eg, teriparatide, bone morphogenetic protein 2) or block a host receptor by sequestering its ligand (eg, etanercept, denosumab) or binding to the receptor directly (eg, anakinra, tocilizumab) (Figure 3). Another virtue of biologics is that they are very specific against one target, and their mechanism of action is completely understood. Thus, biologics are critical tools for gain and loss of function research, and much of what is known about human immunology comes from clinical trials with biologic therapies. Because rheumatoid arthritis is the most prevalent immune-mediated inflammatory disorder (0.5% to 1% of adults, 4.5% of the population older than 55 years, with 5 to 50 per 100,000 new cases annually15), and there is no cure, this disease was the primary indication of many FDA-approved biologics. Moreover, rheumatoid arthritis displays both chronic inflammatory and autoimmune features. Thus, biologics targeting a broad array of soluble factors, receptors, and cell types have been developed (Figure 3). However, there are major shortcomings


of biologic therapy for rheumatoid arthritis that remain significant. The first is the very low bar of efficacy upon which drugs are FDA approved for rheumatoid arthritis, specifically a 20% improvement in the American College of Rheumatology’s criteria (ACR20).16 The other is that all of these biologics are inherently immunosuppressive, such that they cannot be used in combination because of the known risks of opportunistic infections.17 In addition, there are recommendations for a biologic therapy holiday prior to elective surgeries (eg, stopping anti-TNF therapy 2 to 4 weeks before total joint replacement18).

















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May 1, 2023 | Posted by in ORTHOPEDIC | Comments Off on Inflammation and Immunology

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