Humoral Innate Immunity and Acute-Phase Proteins PDF

The n e w e ng l a n d j o u r na l of m e dic i n e Review Article Dan L. Longo, M.D., Editor Humoral Innate Immunity and Acute-Phase Proteins Alberto Mantovani, M.D., and Cecilia Garlanda, Ph...

The n e w e ng l a n d j o u r na l of m e dic i n e Review Article Dan L. Longo, M.D., Editor Humoral Innate Immunity and Acute-Phase Proteins Alberto Mantovani, M.D., and Cecilia Garlanda, Ph.D.​​ T he broad term “inflammation” encompasses a diverse set of From IRCCS Humanitas Research Hos- tissue reactions classically triggered by microbial recognition and by tissue pital, Rozzano, and the Department of Biomedical Sciences, Humanitas Uni- damage.1,2 More recently, it has been recognized that dysmetabolic condi- versity, Pieve Emanuele — both in Milan tions, ranging from diabetes to obesity, elicit overt or subclinical inflammatory (A.M., C.G.); and William Harvey Re- reactions. The general role of inflammatory reactions is in the amplification of search Institute, Queen Mary University, London (A.M.). innate resistance and tissue repair, leading to a return to homeostasis (Fig. 1A). Systemic manifestations of inflammation include fever, alterations in leukocyte N Engl J Med 2023;388:439-52. DOI: 10.1056/NEJMra2206346 counts, cardiovascular reactions, endocrine responses, and reorientation of metabo- Copyright © 2023 Massachusetts Medical Society. lism in association with increased production of a diverse set of molecules referred to as acute-phase proteins.4,5 The prototypic acute-phase protein, C-reactive pro- tein, was originally described as a molecule that was present in the circulation of patients with infections and that was capable of recognizing the C-type polysac- charides of Streptococcus pneumoniae.6,7 The appearance of increased levels of acute- phase proteins in blood and other body fluids (Fig. 1B) is part of a more complex response to local inflammation or to systemic inflammation (e.g., sepsis) that has been referred to as the acute-phase response,5 which is characterized by decreased production of albumin by hepatocytes, reorientation of iron metabolism, and hor- monal changes.4,5 These alterations are also observed in the context of chronic inflammatory conditions and subclinical inflammation. Almost a century after the discovery of C-reactive protein, acute-phase proteins continue to serve as fundamental diagnostic tools that have applications in pa- tients with a range of conditions, including infection, cardiovascular illness, can- cer, neurodegeneration, and dysmetabolism.8-10 During the coronavirus disease 2019 (Covid-19) pandemic, acute-phase proteins such as C-reactive protein, fibrino- gen and its degradation product d-dimer, and ferritin have served as invaluable tools in the day-to-day management of illnesses and as prognostic indicators (Table 1). Progress has been made in dissecting the production, structure, and function of many of these molecules, and the findings have indicated that a fun- damental function of the acute-phase response is to amplify antimicrobial resis- tance and tissue repair, with many of the acute-phase proteins serving as key components of humoral innate immunity (“ante-antibodies”).25 From this general perspective, we review key aspects of the production, structure, and function of selected acute-phase proteins, which continue to represent pillar diagnostic tools that could be integrated more systematically into the molecular signatures that have recently emerged from transcriptomic and proteomic profiles. The C on te x t: Cel lul a r a nd Humor a l Innate Im muni t y Innate immunity is a first line of resistance against microbial pathogens and is involved in the activation of adaptive immune responses, as well as in tissue repair. Innate immunity is made up of a cellular arm and a humoral arm. The molecular strategies used by the cellular arm to sense microbial moieties and tissue damage n engl j med 388;5 nejm.org February 2, 2023 439  The n e w e ng l a n d j o u r na l of m e dic i n e interferon genes (STING), C-type lectins, and A scavenger receptors (Fig. 2). The activation of Homeostatic Infection Tissue injury imbalance these receptors leads to the expression of cyto- Dysmetabolism kines (including interferons and chemokines), Dysbiosis adhesion molecules, and antimicrobial effectors or to the scavenging of microbes through phago- cytosis.1,2,25 The humoral arm of the innate immune sys- Inflammation tem is made up of different classes of molecules, such as pentraxins, collectins, and ficolins, which functionally act as ancestors of antibodies (ante- antibodies) by initiating complement activation, Defense Repair opsonizing microbes and damaged cells, aggluti- nating or neutralizing microbes, and regulating inflammation.25 As discussed below, some of these molecules are key components of the acute- Homeostasis phase response (Table 1) that are rapidly induced in liver cells or other cell types by primary in- flammatory cytokines or microbial moieties. B 30,100 Serum amyloid A Ups t r e a m of the Acu te-Ph a se 30,000 R e sp onse: the C y t ok ine C a sc a de Percentage Change in Plasma Concentration 700 C-reactive protein Sensing of microbial moieties, tissue damage, or 600 dysmetabolism by cellular pattern-recognition molecules sets in motion a cytokine cascade that 500 PTX3 induces amplification and regulation of innate 400 immunity and production of acute-phase pro- α1-Antitrypsin teins, as shown in Figure 3A. Primary inflam- 300 matory cytokines, typically interleukin-1, inter- Fibrinogen leukin-6, and tumor necrosis factor (TNF), 200 Haptoglobin induce production of secondary mediators in 100 tissues (e.g., interleukin-6 itself, chemokines, C3 colony-stimulating factors, endothelial adhesion 0 molecules, prostaglandins, and nitric oxide); Transferrin −100 Albumin these mediators amplify leukocyte recruitment, 0 7 14 21 effector functions, and local innate immunity. Days since Inflammatory Stimulus Amplification of local innate immunity sets the stage for the activation and orientation of adap- Figure 1. Role of Inflammation and Changes in the Circulation of Acute-Phase tive (antigen-specific) immune responses. Proteins. In addition to stimulating chemokine produc- Panel B is adapted from Gitlin and Colten3 with permission from the publisher. PTX3 denotes pentraxin 3. tion and favoring the transition from acute to chronic inflammation, interleukin-6 is a potent inducer of the production of acute-phase pro- involve cell-associated pattern-recognition mol- teins in the liver through reprogramming and ecules located in different cellular compartments reorientation of metabolic functions (e.g., de- (plasma membrane, endosomes, and cytoplasm) crease in albumin production and increased and belonging to different molecular families, production of acute-phase proteins). Inflamma- including toll-like receptors (TLRs), nucleo- tory cytokines also act on the central nervous tide-binding oligomerization domain (NOD)– system through their activation of the hypo- like and retinoic acid–inducible gene I (RIG-I)– thalamus–pituitary–adrenal axis, resulting in like receptors, inflammasomes, stimulator of production of adrenocorticotropic hormone and 440 n engl j med 388;5 nejm.org February 2, 2023  Humor al Innate Immunity and Acute-Phase Proteins Table 1. Main Acute-Phase Proteins and Their Role in Covid-19.* Degree and Type of Change in Inflammatory Role or Roles in Covid-19 and Associated Function and Protein or Proteins Conditions† Conditions‡ Humoral innate immunity C-reactive protein ↑↑↑↑ Association with death, ICU admission, need for interleukin-6 inhibition, and PASC11-14 Serum amyloid P ↑ or → ND Serum amyloid A ↑↑↑↑ Association with severity15 PTX3 ↑↑↑ Association with death, lung lesions on CT, response to interleukin-6 inhibition, intu­ bation, thrombotic events, and PASC16-19 C1q, C3, and C4 ↑ Association with pathogenesis20,21 C4-binding protein ↑ ND Mannose-binding lectin ↑↑ or → Viral inhibition, association with thromboem- bolism22 Interleukin-1Ra ↑↑ Association between anti–interleukin-1Ra auto­ antibodies and severity, MIS-C, or myo­ carditis after SARS-CoV-2 vaccination23 Coagulation or tissue repair and remodeling Fibrinogen ↑↑ Association of d-dimer with thromboembolism14 Prothrombin → ND Fibronectin ↑ or → ND α2-Macroglobulin ↑ ND Antithrombin III ↓ ND α1-Antitrypsin ↑↑ ND α1-Antichymotrypsin ↑↑ ND Urokinase-type plasminogen activator ↑ ND Thrombopoietin ↑↑ ND Iron metabolism Transferrin ↓ ND Ferritin ↑↑ Association with ICU admission and mechanical ventilation14,24 Haptoglobin ↑↑ ND Hemopexin ↑ ND Hepcidin ↑↑ ND Other carrier proteins Albumin ↓ ND Ceruloplasmin ↑ or → ND Apolipoproteins ↓ ND α1-Acid glycoprotein ↑↑ ND * Covid-19 denotes coronavirus disease 2019, CT computed tomography, ICU intensive care unit, MIS-C multisystem inflammatory syndrome in children, ND not determined, PASC postacute sequelae of Covid-19, PTX3 pentraxin 3, and SARS-CoV-2 severe acute respiratory syndrome coronavirus 2. † Upward-pointing arrows (↑) and downward-pointing arrows (↓) indicate increases and decreases in concentration, re- spectively; a right-pointing arrow (→) indicates no change. Greater numbers of upward-pointing arrows indicate greater increases in concentration. ‡ The references shown are selected references related to Covid-19. n engl j med 388;5 nejm.org February 2, 2023 441  The n e w e ng l a n d j o u r na l of m e dic i n e Innate Immunity First line of resistance against microbial pathogens Activates adaptive immune responses Activates tissue repair Cellular Innate Immunity Humoral Innate Immunity Detection of microbial moieties, tissue damage, and dysmetabolism Complement activation Opsonization Agglutination or neutralization of microbes Microbial moieties Regulation of inflammation CpG DNA, viral ssRNA or dsRNA SP-D Lipopeptides, Integrin C-type SP-A LPS, or PGN Scavenger FcγR lectin Ficolins receptor PTX3 MBL TLR3, CRP SAP 7, 8, or 9 Collectins Phagocytosis C1q Short and long TLR1, 2, 4, or endocytosis pentraxins 5, or 6 TRIF Viral dsRNA TRIF MyD88 MyD88 Microbial Interleukin-1 moieties RIG-I-like NF-κB NF-κB Inflammasome receptor C YT O PLA SM IRF3 IRF3 Viral DNA STING cGAS NF-κB NF-κB APPs and cytokines Endoplasmic IRF3 IRF3 Type 1 interferons cGMP reticulum NU CLEU S Professional Cells Involved in Innate Immunity Nonprofessional Cells Involved in Innate Immunity Monocytes Eosinophils Epithelial cells Basophils Natural Innate Stromal cells Macrophages Neutrophils killer cells lymphoid cells Endothelial cells Conventional Plasmacytoid dendritic cell dendritic cell 442 n engl j med 388;5 nejm.org February 2, 2023  Humor al Innate Immunity and Acute-Phase Proteins Figure 2 (facing page). Innate Immunity — a Cellular proteins4 (Fig. 3A). Approximately 200 acute- Arm and a Humoral Arm. phase proteins are produced — mainly by hepa- Cellular sensors of tissue damage, infection, and dys- tocytes, but other cell types also contribute to metabolism are strategically localized on the cell sur- the acute-phase reaction. These cell types in- face, in the endosomal compartment, and in the cyto- clude organ-infiltrating monocytes and tissue- plasm, in both professional innate immune cells (i.e., those with innate immunity as their principal function) resident macrophages such as Kupffer cells, he- and nonprofessional innate immune cells (i.e., those patic stellate cells, and endothelial cells, all of with other principal functions). The latter include hepa- which are sources of proinflammatory cytokines tocytes, a major source of acute-phase proteins. Under that activate acute-phase protein synthesis by homeostatic conditions and in response to inflamma- hepatocytes.28 tion, components of the humoral arm of innate immu- nity are produced. These molecules serve complex Evidence suggests that in addition to hepato- functions, including immune resistance, by activating cytes, cells in peripheral tissues can produce complement and having opsonic activity (ante-antibod- some acute-phase proteins (Fig. 3B). For instance, ies). APP denotes acute-phase protein, cGAS cyclic macrophages and endothelial cells can produce GMP–AMP synthase, cGMP cyclic guanosine mono- complement components,29 serum amyloid A phosphate, CRP C-reactive protein, dsRNA double- stranded RNA, IRF interferon regulatory factor, LPS (SAA),30 iron transporters, α1-antitrypsin,31 and ­lipopolysaccharide, MBL mannose-binding lectin, interleukin-1Ra. The pentraxin relative of C-reac- MyD88 myeloid differentiation primary response 88, tive protein, pentraxin 3 (PTX3), is released NF-κB nuclear factor kappa B, PGN peptidoglycan, mainly in peripheral tissues by diverse cell types, RIG-I retinoid acid-inducible gene I, SAP serum amy- most notably phagocytes and endothelial cells, loid P, SP-A surfactant protein A, SP-D surfactant pro- tein D, ssRNA single-stranded RNA, STING stimulator on induction by microbial moieties or inflam- of interferon genes, TLR toll-like receptor, TRIF toll/­ matory cytokines. At a local tissue level, local interleukin-1 receptor–domain–containing adapter-­ production complements the function of circu- inducing interferon-β. lating acute-phase proteins produced by hepato- cytes (Fig. 3B). For instance, adipose tissue is an glucocorticoid hormones. Glucocorticoid hor- important source of the overall systemic concen- mones, among their many functions, act as tration of acute-phase proteins in response to negative regulators of inflammation by suppress- proinflammatory stimuli (interleukin-1 and inter- ing, for instance, interleukin-1 and inducing the leukin-6). Adipocytes express large amounts of interleukin-1 decoy receptor interleukin-1R2.26 complement factors (C3, D, and B), αl-acid glyco- Antiinflammatory cytokines (interleukin-10, trans- protein, and lipocalin-2, as well as plasminogen forming growth factor β, and interleukin-1Ra) activator inhibitor 1 (PAI-1) and serum amyloid are also part of pathways of negative regulation A3 (SAA3).32 In myopathy, skeletal muscle wast- (Fig. 3A). Among these antiinflammatory cyto- ing, and atrophy associated with critical illness, kines, interleukin-1Ra, which acts as an interleu- locally produced interleukin-6 and TNF contrib- kin-1R antagonist, has classically been consid- ute to the induction of acute-phase proteins in ered a liver-derived acute-phase protein27 and is muscle cells. In this condition, primary inflam- a product of macrophages and other cell types in matory cytokines and serum amyloid A1 (SAA1) tissues. Interleukin-1 and interleukin-6 are the contribute to muscle atrophy.33 key regulators of acute-phase protein synthesis in the liver through their activation of a network Mol ecul e s a nd F unc t ions of transcription factors (signal transducer and activator of transcription 3 [STAT3], nuclear fac- Pentraxins tor κB, and CCAAT/enhancer-binding proteins) Pentraxins are a family of evolutionarily con- and methylation of CpG motifs in the binding served proteins characterized by a cyclic mul- sites of these transcription factors.28 timeric structure and by the presence of a conserved 200-amino-acid pentraxin domain. Hepat ic a nd Nonhepat ic Source s C-reactive protein (also called PTX1) and serum of Acu te-Ph a se Pro teins amyloid P component (SAP, or PTX2) are penta- meric short pentraxins.34 PTX3 is an octameric The liver has classically been considered the molecule, and each protomer has a pentraxin- source of the elevated blood levels of acute-phase like domain associated with a long N-terminal n engl j med 388;5 nejm.org February 2, 2023 443  The n e w e ng l a n d j o u r na l of m e dic i n e A Detection by Pattern-Recognition Molecules Microbes Dysbiosis Tissue Damage Dysmetabolism Cytokine Cascade Production of ACTH TGF-β Glucocorticoids Interleukin-10 and glucocorticoids − − − Mediators Mediators TNF and interleukin-1 Secondary Primary Interleukin-6 Hypothalamus–pituitary– adrenal axis + Chemokines CSFs Prostaglandins; nitric oxide Production of acute-phase Leukocyte enrollment proteins in the liver and survival Basophils, neutrophils, and eosinophils Monocytes and macrophages Inflammation and amplification of innate immunity Amplification of systemic Activation and orientation Innate and adaptive innate immunity of adaptive immunity lymphoid cells B Detection by Pattern-Recognition Molecules (e.g., TLR and inflammasome) Microbes Tissue Damage Cellular Sources of Acute-Phase Proteins and Function TNF, interleukin-1, and interleukin-6 Hepatocytes Conventional Macrophages Neutrophils Stromal cells Adipocytes Endothelial cells dendritic cells Acute-Phase Proteins Derived from Liver Cells Derived from Leukocytes Derived from Cells in Both Categories or Stromal Cells Complement α1-AT SAA C1q MBL Fibronectin Fibrinogen CRP SAP molecules PTX3 C3 C5 Tissue Repair Humoral Innate Immunity Coagulation Pathogen and tissue-damage recognition Extracellular remodeling Complement activation Opsonization 444 n engl j med 388;5 nejm.org February 2, 2023  Humor al Innate Immunity and Acute-Phase Proteins Figure 3 (facing page). The Cytokine Cascade and Cellular ment-dependent opsonization, short pentraxins Sources and Functions of Acute-Phase Proteins. and PTX3 promote phagocytosis of microbes and Panel A shows the cytokine cascade set in motion by apoptotic cells by interacting with FcγR, partic- pattern-recognition molecules; this process involves ularly with FcγRIII (also called CD16) and the production of primary and secondary mediators, FcγRII (CD32)40 (Fig. 2). They also interact with activation of the acute-phase response, and promotion complement regulators, such as factor H and of leukocyte recruitment and leads to amplification of local and systemic innate immunity, as well as to the C4BP, thereby promoting regulation of comple- activation and orientation of adaptive immune responses. ment-dependent inflammation. Inflammatory cytokines also promote the expression Genetic polymorphisms are associated with of negative regulators of inflammation (interleukin-10, increased C-reactive protein levels, and C-reac- transforming growth factor beta [TGF-β], and interleu- tive protein levels in blood are associated with kin-1Ra) and the activation of the hypothalamus–pitu- itary–adrenal axis, which results in production of adre- the risk of coronary heart disease.8,9 This asso- nocorticotropic hormone (ACTH) and glucocorticoid ciation suggested a pathogenetic role for C-reac- hormones. As shown in Panel B, in addition to hepato- tive protein in atherosclerosis. Mendelian ran- cytes, other cell types contribute to the synthesis of domization analysis in a large cohort of patients acute-phase proteins, which contribute to humoral with coronary disease showed that genetically ­innate immunity and tissue repair. α1-AT denotes α1- antitrypsin, CSF colony-stimulating factor, SAA serum increased concentrations of C-reactive protein amyloid A, and TNF tumor necrosis factor. are unrelated to conventional risk factors and the risk of cardiovascular events.41 SAP binds and stabilizes all forms of amyloid domain unrelated to those of other known pro- fibrils, contributing to amyloidosis.34,42 SAP also teins.35 binds extracellular matrix components, such as C-reactive protein is a prototypic liver-derived laminin, type IV collagen, fibronectin, and pro- acute-phase protein in humans, whereas SAP is teoglycans, thereby regulating extracellular ma- the main acute-phase protein in mice. In humans, trix deposition and inhibiting fibrosis. In idio- C-reactive protein plasma levels increase by as pathic pulmonary fibrosis, human SAP (PRM-151) much as 1000 times in response to an acute- improves lung function43 by inhibiting alterna- phase stimulus, in particular to interleukin-6, tive activation of macrophages and fibrocyte whereas SAP is constitutively present in plasma. differentiation. In addition, PTX3 interacts with In contrast, PTX3 is rapidly induced in response extracellular matrix proteins (TNF-α–induced to interleukin-1 and TNF or microbial compo- protein 6 and inter–α-trypsin inhibitor), fibrino- nents in various cell types — in particular, myelo- gen or fibrin, and plasminogen, which explains monocytic cells (monocytes, macrophages, den- its involvement in matrix remodeling in tissue dritic cells), vascular and lymphatic endothelial damage and repair.44 cells, and stromal cells.35 Neutrophils synthesize PTX3 plasma concentrations increase rapidly PTX3 during myelopoiesis, store it in lactoferrin- during a number of infections and are positively positive granules, and rapidly release it after associated with disease severity and the risk of microbial recognition.36 Thus, PTX3 differs from death,45-48 as discussed below for Covid-19. PTX3 short pentraxins in terms of structure, cell source, plasma levels also reflect the severity of inflam- and regulation. matory vascular diseases ranging from athero- C-reactive protein, SAP, and PTX3 bind various sclerosis to vasculitis.49 In inflammatory condi- bacteria, fungi, and viruses, promoting innate tions, PTX3 levels increase earlier than C-reactive immune responses to these pathogens.25,34,37,38 protein levels, as shown in Figure 1B. The dif- Pentraxins also bind to phospholipids and small ferent kinetics of the appearance of PTX3 and nuclear ribonucleoproteins in apoptotic cells, C-reactive protein may well reflect their different promoting the disposal of these cells in a non- cellular sources. PTX3 is stored in neutrophil gran- inflammatory mode.39 ules, ready-made for release, and PTX3 serves as an C-reactive protein, SAP, and PTX3 interact immediate early gene in tissues, with its tran- with different complement molecules (e.g., C1q, scription induced by TLR agonists and inflamma- ficolins, and mannose-binding lectin [MBL]), tory cytokines. In contrast, C-reactive protein pro- which leads to enhanced and broader recogni- duction in the liver is downstream of the cytokine tion potential. In addition to promoting comple- cascade, which results in a later appearance. n engl j med 388;5 nejm.org February 2, 2023 445  The n e w e ng l a n d j o u r na l of m e dic i n e PTX3 and SAP genetic polymorphisms have SAA-derived C-terminal truncated AA protein been associated with susceptibility to fungal and folding into extremely hydrophobic β sheets that bacterial infections38,48,50,51 and to lung granulo- aggregate in oligomers, which generate insolu- ma formation in sarcoidosis through regulation ble, proteolysis-resistant fibrils.57 of complement.52 Thus, results of mechanistic analyses, evidence from gene-targeted mice, and The Complement System findings from analyses of human genetic poly- The complement system is an evolutionarily con- morphisms are consistent with the view that the served central player in humoral innate immu- pentraxin trio of C-reactive protein–SAP–PTX3 nity. It consists of approximately 50 soluble plays a role in the amplification of innate resis- molecules, mostly produced by the liver and tance to selected pathogens and in the regula- normally found in the circulation, and cell-asso- tion of tissue remodeling. ciated receptors, which are expressed by several cell types.29,58 Serum Amyloid A The liver is the major site for the synthesis of Members of the SAA family are major acute- most complement molecules. Among them, both phase proteins in humans. In humans, four genes activating molecules (C3, C4, C9, and factor B) encode different members of the family; SAA1 and negative regulators (C1 inhibitor and C4BP) and SAA2 are typical liver-derived acute-phase are up-regulated during an acute-phase reaction, proteins and are collectively termed A-SAA. Extra- which underlines the relevance of activating bal- hepatic synthesis of A-SAA in joints accounts for anced complement-mediated responses. However, high SAA levels in the synovial fluid, in addition their synthesis increases modestly as compared to high systemic plasma levels.53 In the small with that of major acute-phase reaction mole- intestine, SAA is induced in epithelial cells by cules and peaks at late time points4 (Fig. 1B). In interleukin-22 and promotes local T helper 17 addition to hepatocytes, other cell types, includ- cell differentiation and effector function, favor- ing monocytes, macrophages, endothelial cells, ing barrier integrity.54 fibroblasts, and adipocytes, can be local sources Cytokine-like functional activities have been of complement proteins such as C1q, C3, and reported for SAA family members, including C529 (Fig. 3B). chemotaxis caused by direct interaction with the G protein–coupled formyl peptide receptors. In Mannose-Binding Lectin addition, the scavenger receptor B-I (CD36) acts MBL is a liver-derived C-type plasma lectin, a as an endocytic SAA receptor and is involved in class of pattern-recognition molecules composed SAA-mediated immune and inflammatory func- of a Ca2+-type lectin domain (also called the tions. A-SAA also reportedly induces M2-like carbohydrate-recognition domain) and a collagen- (antiinflammatory) skewing of macrophages like domain,59 acting as a humoral pattern-recog- and opsonizes gram-negative pathogenic bacte- nition molecule with high affinity for mannose ria, promoting their clearance and innate resis- and N-acetyl glucosamine exposed on microbes. tance to infections.55 MBL interacts with these carbohydrate moieties Because of the massive increase in its plasma through the lectin domain, opsonizing patho- concentrations during inflammation, A-SAA has gens for phagocytosis and leading to activation been used as a marker in several inflammatory of MBL-associated serine proteases, thus initiat- conditions, such as rheumatoid arthritis, cardio- ing the complement cascade through the lectin vascular diseases, cancer, and infections, includ- pathway. Within MBL2, the gene encoding human ing severe acute respiratory syndrome corona- MBL, three point mutations have been found in virus 2 (SARS-CoV-2) infection.30,53,56 Long-term exon 1, which encodes the MBL collagenous re- or recurrent high plasma SAA concentrations gion; in addition, several polymorphisms have (e.g., due to tuberculosis or rheumatoid arthritis) been found in the promoter region. These muta- in association with SAA1 allelic variants or other, tions and polymorphisms affect the function unknown factors can lead to amyloid A (AA) and plasma concentration of the molecule. The amyloidosis, a condition caused by the accumu- combination of the promoter haplotypes and lation of AA fibrils in several organs, including structural mutations results in MBL deficiency, the kidneys, spleen, and liver, impairing their which occurs in approximately 25% of persons function. AA fibrils form as a consequence of and is associated with increased susceptibility to 446 n engl j med 388;5 nejm.org February 2, 2023  Humor al Innate Immunity and Acute-Phase Proteins selected infections, particularly in children with membranes, promoting lipid peroxidation. Up- primary or secondary immunodeficiency.60 MBL regulation of haptoglobin and hemopexin in was originally defined as an acute-phase protein acute-phase reactions favors protection against on the basis of the up-regulation of MBL2 in liver- heme-mediated oxidative stress, iron loss in biopsy specimens from patients with inflamma- inflammatory conditions associated with hemo- tory conditions. However, subsequent studies lysis, and infections by preventing the utilization have shown that in most persons with coding of iron by pathogens. mutations, MBL is not up-regulated in the acute phase of infectious conditions. For instance, in Acute-Phase Proteins, Coagulation, studies involving patients with sepsis or pneu- and Tissue Repair monia, MBL behaved as a positive or negative A number of acute-phase proteins are related to acute-phase protein or did not change during the coagulation cascade. Fibrinogen and its down- hospitalization, with its behavior depending stream degradation products (d-dimer and other mainly on the genotype of exon 1 and the pro- fibrin degradation products) are widely used as moter61,62 and possibly on other single-nucleotide diagnostic markers in inflammatory conditions, polymorphisms in regulatory regions.22 including Covid-19. Coagulation and tissue repair are strictly connected processes. The fibrin mesh Acute-Phase Proteins and Iron Homeostasis formed downstream of the coagulation cascade Several acute-phase proteins are involved in the serves as a provisional matrix essential for tissue metabolism of iron, a nutrient required for a repair. Its timely removal by means of fibrinoly- number of host-cell functions as well as for the sis is a prerequisite for subsequent steps in ma- growth of microbial pathogens. The general func- trix maturation. The acute-phase reaction fuels tions of acute-phase proteins in iron metabolism components involved in coagulation (e.g., fi- include binding to the nutrient, thus preventing brinogen) and extracellular matrix formation utilization of circulating free iron by pathogens, (fibronectin) (Table 1). PTX3, unlike its relative and retention of iron inside cells. Therefore, the C-reactive protein, engages in a tripartite inter- complex regulation of iron metabolism results action with fibrinogen and plasminogen, promot- in metabolic resistance to selected pathogens. ing the timely degradation of the provisional fibrin The acute-phase proteins involved in free iron mesh and subsequent tissue repair.44 In addition control include the circulating peptide hormone to extracellular matrix components, inhibitors hepcidin, ferritin, haptoglobin, and hemopexin, of proteolytic enzymes (e.g., α1-antitrypsin, α2- which are up-regulated in the acute-phase reac- macroglobulin, and α1-acid glycoprotein) are tion, whereas transferrin is a negative acute-phase produced during the acute-phase reaction, and protein that is down-regulated during the acute these inhibitors may limit tissue damage. For phase (Table 1). Hepcidin binds the transmem- instance, α1-antitrypsin has host protective brane protein ferroportin, regulating the release functions in autoimmunity and infection.31,63 of iron from cells to plasma. Ferritin normally Extracellular matrix proteins, including fibrino- directly reflects iron levels in blood; however, in gen and fibronectin, bind microbes and facili- contrast to iron-deficiency anemia, anemia as- tate their clearance by phagocytes. The ancestral sociated with chronic inflammatory diseases is function of fibrinogen domain–containing mole- characterized by higher levels of ferritin than cules was defense.25 Therefore, the production of normal because of its induction by the acute- some extracellular matrix proteins during sys- phase reaction. Indeed, a high plasma concen- temic inflammation is at the intersection of tration of ferritin is observed in patients with tissue repair and innate immunity. severe pathologic inflammatory conditions, in- cluding macrophage-activation syndrome, septic C ov id -19 shock, and Covid-19, in which ferritin is used as a marker of severity and prognosis (see below). Innate immune recognition of SARS-CoV-2 acts Haptoglobin and hemopexin are acute-phase as a fundamental first line of resistance, triggers proteins that act as soluble scavengers of free adaptive immunity, and drives the immunopatho- hemoglobin and heme, respectively. Free heme is logic effects of infection.64 The cellular sensors highly toxic because it is a source of redox-active involved in the innate response to SARS-CoV-2 in- iron and has the ability to intercalate into lipid clude membrane C-type lectins that recognize spike n engl j med 388;5 nejm.org February 2, 2023 447  The n e w e ng l a n d j o u r na l of m e dic i n e protein65; endosomal TLR3, TLR7, and TLR8, Figure 4 (facing page). Recognition of SARS-CoV-2 by which recognize viral nucleic acids; the cytoplas- Cellular and Humoral Pattern-Recognition Molecules, mic cyclic GMP–AMP synthase (cGAS)–STING Including Acute-Phase Proteins. pathway; and the inflammasome (Fig. 4). The Severe acute respiratory syndrome coronavirus 2 (SARS- SARS-CoV-2–encoded open reading frame 8 (ORF8) CoV-2) proteins and nucleic acids are recognized by cellu- lar receptors involved in innate immunity, including has recently been shown to inhibit interferon C-type lectins, TLRs, cGAS–STING, and the inflamma- production through epigenetic mechanisms.66 some. Open reading frame 8 (ORF8) inhibits interferon SARS-CoV-2 components are recognized by select- production through epigenetic mechanisms. The hu- ed acute-phase proteins. MBL binds the spike moral pattern-recognition molecules MBL and PTX3 protein of all variants tested and has antiviral bind glycosylated spike and the viral nucleocapsid, ­respectively. activity.22 Moreover, it activates the complement lectin pathway, thus possibly contributing to im- munopathologic effects in advanced disease. PTX3, unlike C-reactive protein and SAP, binds PTX3 has emerged as a strong prognostic marker the viral nucleoprotein,22 but the actual in vivo and independent predictor of death within 28 days function of this interaction has not been defined. in hospitalized patients. PTX3 was found to be Although the clinical significance of virus expressed by myeloid cells in peripheral blood recognition by selected acute-phase proteins re- and lungs and by lung endothelial cells in pa- mains to be fully elucidated, these molecules have tients with Covid-19.16 The strong independent served as invaluable diagnostic tools throughout prognostic significance of PTX3, which is better the pandemic, in contexts ranging from outpa- than that of C-reactive protein, interleukin-6, tient clinics to intensive care units (ICUs) (Ta- ferritin, or d-dimer, may reflect an integration ble 1). C-reactive protein, procalcitonin, and of myeloid and microvascular endothelial cell ferritin have been used extensively, and in most activation. studies, high plasma concentrations at hospital The selection of patients for different thera- admission have been associated with severe dis- pies at different stages of the disease and their ease and poor survival.11-14 The concentration of follow-up remain formidable challenges. Eleva- d-dimer downstream of fibrinogen has been tions in C-reactive protein levels combined with positively correlated with areas of hypoperfusion the determination of a need for supplemental in patients with acute respiratory distress syn- oxygen have been used to select patients who may drome, a finding consistent with thromboem- benefit from anti–interleukin-6 therapy.72 In a bolic disease, and has been associated with small study (involving 30 patients), the response higher mortality.67 Dysregulated iron homeosta- to treatment with an anti–interleukin-6 mono- sis, which is common in hospitalized patients clonal antibody (siltuximab) was measured with Covid-19, as reflected by the presence of with the use of a range of biomarkers. Levels of anemia and an increased ferritin:transferrin ra- C-reactive protein were decreased irrespective of tio, has been found to predict ICU admission clinical benefit, reflecting the inhibition of pro- and receipt of mechanical ventilation.24 The con- duction of this acute-phase protein by the liver, centration of complement components is increased unrelated to tissue inflammation. In contrast, in patients with Covid-19, a finding consistent PTX3 and interleukin-8, which are produced in with a role of this pathway in immunopatho- tissues, were better correlates of clinical re- logic effects.20 The complement pathway has sponse.68 emerged as a therapeutic target in Covid-19, Prediction of disease progression represents a with encouraging preliminary results in small holy grail for timely intervention. A low-cost cohort studies showing a reduced acute-phase signature that included C-reactive protein as an reaction, reduced thrombin activity, and reduced indicator of systemic inflammation, PTX3 as a neutrophil extracellular trap generation in asso- correlate of tissue reaction, and lactate dehydro- ciation with complement inhibition.21 In a series genase as an indicator of cell and tissue damage of independent studies based on conventional was found to correlate with the severity of le- immunoassays16,17,68-70 or proteomic approaches,71 sions on computed tomography and subsequent 448 n engl j med 388;5 nejm.org February 2, 2023  Humor al Innate Immunity and Acute-Phase Proteins SARS-CoV-2 Glycosylated spike protein ORF8 Viral RNA Nucleocapsid Membrane protein Envelope protein Cellular Innate Immunity Humoral Innate Immunity Nucleocapsid Glycosylated spike protein Glycosylated spike protein Viral RNA SARS-CoV-2 PTX3 MBL SARS-CoV-2 proteins C-type lectin TLR3, Complement activation 7, 8, or 9 Endosome or Viral inhibition TLR1, 2, 4, phagosome Viral entry 5, or 6 TRIF Inflammasome Viral RNA MyD88 TRIF MyD88 Interleukin-1 RIG-I-like receptor NF-κB NF-κB Damaged IRF3 IRF3 C YT O PL AS M mitochondrial DNA STING cGAS NF-κB NF-κB APPs and cytokines Endoplasmic IRF3 IRF3 Type 1 interferons cGMP reticulum NU CLE U S ORF8 Disruption of epigenetic regulation; decreased interferon-γ n engl j med 388;5 nejm.org February 2, 2023 449  The n e w e ng l a n d j o u r na l of m e dic i n e disease progression in patients with paucisymp- crobes and dead cells by activating and regulat- tomatic Covid-19.18 Integration of low-tech, low- ing the complement cascade and by mediating cost measurement of selected acute-phase pro- opsonic activity. Increased production of matrix teins with molecular signatures may pave the molecules (fibrinogen and fibronectin) and pro- way to the development of tools allowing more tease inhibitors during the acute-phase response patient-tailored early approaches. may be viewed as a general mechanism to pro- Postacute sequelae of Covid-19 (PASC), also mote tissue repair. Moreover, changes in iron known as “long Covid,” is a challenge for pa- metabolism have broad implications at a sys- tients and for health care systems. The patho- temic (metabolic resistance) and cellular level.79 genesis of PASC is complex and depends on Thus, acute-phase proteins, and by and large the several driving factors, including the persistence acute-phase response, are an essential compo- of SARS-CoV-2 in different organs; reactivation and nent of humoral innate immunity, promoting response to unrelated viruses, such as Epstein– antimicrobial resistance and tissue repair. Barr virus; autoimmunity; sustained inflamma- The recognition that some acute-phase pro- tion; and microvascular thrombosis.73-75 Fatigue, teins are more than biomarkers raises the possi- muscle weakness, and exercise intolerance are bility that they may represent therapeutic tools among the most frequent symptoms of long or targets. SAP binds to all forms of amyloid Covid. This clinical picture is reminiscent of a fibrils and is a therapeutic target in amyloidosis condition known as chronic fatigue syndrome and neurodegeneration.34,42,80 However, on the ba- or myalgic encephalomyelitis, which occurs after sis of its inhibitory effect on fibrocyte differen- viral infections, in which acute-phase proteins tiation, SAP has entered clinical assessment for have emerged as correlates of disease activity.73,76 the treatment of idiopathic pulmonary fibrosis43 In a recent proteomic study aimed at defining a and is being evaluated in randomized phase 3 biomarker associated with subsequent develop- trials (ClinicalTrials.gov numbers, NCT04594707 ment of PASC, a set of acute-phase proteins, includ- and NCT04552899). Genetic polymorphisms at ing C-reactive protein and molecules involved in the SAP and PTX3 loci and evidence from pre- iron metabolism, emerged as part of an inflam- clinical studies point to the therapeutic potential mation and stress-response signature predictive of these molecules for aspergillus infections, of long Covid.77 Profound perturbations of myeloid- which pose a major clinical challenge.38,48 MBL cell function were observed 8 months after mild- has been administered to patients with genetic to-moderate Covid-19. A set of biomarkers deficiencies81 and has been recently shown to (interferon-β, interferon-γ, interferon-λ, inter- recognize the spike protein of known SARS- leukin-6, and PTX3) was associated with PASC.19 CoV-2 variants and to mediate resistance against The borders of the long-Covid universe and the SARS-CoV-2.22 Thus, human genetics, safety, and diversity of organ involvement remain ill-defined. preclinical findings call for efforts to explore Changes in acute-phase protein levels together the potential of acute-phase proteins for future with emerging signatures74,78 may help to define therapeutic applications. the actual borders of this universe, its diversity, Comprehensive approaches that take advan- and the prognosis of organ involvement. tage of state-of-the-art technology have identi- fied candidate signatures associated with the risk and clinical course of Covid-19,19,74,77,78 and some C onclusions of the molecules discussed here are part of these Since the discovery of C-reactive protein, acute- signatures. Integration of classic validated bio- phase proteins have been invaluable tools at the markers in emerging signatures and their rigor- bedside in a wide range of diseases, including ous assessment in large population studies with Covid-19 and long Covid,11-14,16 which points to sustainable technology hold promise for a “back inflammation as a metanarrative of medicine at to the future” for acute-phase proteins 100 years present and in the foreseeable future.10,26 Acute- on from their initial discovery.6,7 phase proteins have emerged as more than inno- Disclosure forms provided by the authors are available with cent bystanders of acute and chronic inflam- the full text of this article at NEJM.org. mation. Many of these molecules recognize We thank Dr. Antonio Voza (head of the emergency depart- ment, Humanitas Research Hospital) and Prof. Maurizio Cec- microbial moieties and damaged cells or tissues. coni (head of the intensive care unit, Humanitas Research Hos- These ante-antibodies promote disposal of mi- pital) for discussion and suggestions. 450 n engl j med 388;5 nejm.org February 2, 2023  Humor al Innate Immunity and Acute-Phase Proteins References 1. Medzhitov R. The spectrum of in- in COVID-19. Nat Immunol 2021;​22:​19- α1-Antitrypsin binds to the glucocorti- flammatory responses. Science 2021;​374:​ 24. coid receptor with anti-inflammatory and 1070-5. 17. Lapadula G, Leone R, Bernasconi DP, antimycobacterial significance in macro- 2. Nathan C. Nonresolving inflamma- et al. Long pentraxin 3 (PTX3) levels pre- phages. J Immunol 2022;​209:​1746-59. tion redux. Immunity 2022;​55:​592-605. dict death, intubation and thrombotic 32. Lin Y, Rajala MW, Berger JP, Moller 3. 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