Humoral Innate Immunity and Acute-Phase

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

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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.

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

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

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

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.

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, favoring 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

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

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

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

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.

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Humoral Innate Immunity and Acute-Phase

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The n e w e ng l a n d j o u r na l of m e dic i n e

Dan L. Longo, M.D., Editor

Humoral Innate Immunity and Acute-Phase

The C on te x t: Cel lul a r a nd Humor a l Innate Im muni t y

n engl j med 388;5 nejm.org February 2, 2023 439

interferon genes (STING), C-type lectins, and

700 C-reactive protein

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Table 1. Main Acute-Phase Proteins and Their Role in Covid-19.*

Degree and Type

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Cellular Innate Immunity Humoral Innate Immunity

Detection of microbial moieties, tissue damage, and dysmetabolism Complement activation

Agglutination or neutralization of microbes

Lipopeptides, Integrin C-type SP-A

RIG-I-like NF-κB NF-κB Inflammasome

Endoplasmic IRF3 IRF3 Type 1 interferons

Monocytes Eosinophils Epithelial cells

Natural Innate Stromal cells

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Microbes Dysbiosis Tissue Damage Dysmetabolism

TNF and interleukin-1

Production of acute-phase Leukocyte enrollment

Amplification of systemic Activation and orientation Innate and adaptive

Microbes Tissue Damage

Cellular Sources of Acute-Phase Proteins

Hepatocytes Conventional Macrophages Neutrophils Stromal cells Adipocytes Endothelial cells

Tissue Repair Humoral Innate Immunity

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Glycosylated spike protein

Cellular Innate Immunity Humoral Innate Immunity

TLR3, Complement activation

Damaged IRF3 IRF3

Endoplasmic IRF3 IRF3 Type 1 interferons

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