Exploring the Intricate Internet of Host Defenses: How the Immune System Safeguards the Physique from Pathogenic Threats

Exploring the Intricate Internet of Host Defenses: How the Immune System Safeguards the Physique from Pathogenic Threats

 

PRINCIPLES OF HOST DEFENSES

Host defenses are composed of two complementary, incessantly

interacting techniques: (1) innate (nonspecific) defenses, which

shield in opposition to microorganisms basically; and (2) adap-

tive (particular) immunity, which protects in opposition to a specific

microorganism.

Innate defenses might be categorised into three main classes:

(1) bodily limitations, resembling intact pores and skin and mucous mem-

branes; (2) phagocytic cells, resembling neutrophils, macrophages,

and pure killer cells; and (3) proteins, resembling complement,

lysozyme, and interferon. Determine 8–1 reveals the function of a number of

parts of the nonspecific defenses within the early response to

bacterial an infection. Adaptive immunity is mediated by antibod-

ies and T lymphocytes. Chapter 57 describes these host defenses

in additional element.

There are two primary kinds of host defenses in opposition to micro organism:

the pyogenic response and the granulomatous response. Cer-

tain micro organism, resembling Staphylococcus aureus and Streptococcus

pyogenes, are defended in opposition to by the pyogenic (pus-producing)

response, which consists of antibody, complement, and neu-

trophils. These pyogenic micro organism are sometimes referred to as extracellular

pathogens as a result of they don’t invade cells. Different micro organism, such

as Mycobacterium tuberculosis and Listeria monocytogenes, are

defended in opposition to by the granulomatous response, which con-

sists of macrophages and CD4-positive (helper) T cells. These

micro organism are sometimes referred to as intracellular pathogens as a result of they’ll

invade and survive inside cells.

INNATE (NONSPECIFIC) IMMUNITY

Pores and skin & Mucous Membranes

Intact pores and skin is the primary line of protection in opposition to many organisms.

Along with the bodily barrier offered by pores and skin, the fatty

acids secreted by sebaceous glands within the pores and skin have antibacterial

and antifungal exercise. The elevated fatty acid manufacturing that

happens at puberty is assumed to clarify the elevated resistance

to ringworm fungal infections, which happens at the moment. The

low pH of the pores and skin (between 3 and 5), which is because of these fatty

acids, additionally has an antimicrobial impact. Though many organ-

isms reside on or within the pores and skin as members of the traditional flora, they

are innocent so long as they don’t enter the physique.

A second vital protection is the mucous membrane of

the respiratory tract, which is lined with cilia and coated with

mucus. The coordinated beating of the cilia drives the mucus

as much as the nostril and mouth, the place the trapped micro organism might be

expelled. This mucociliary equipment, the ciliary elevator, can

be broken by alcohol, cigarette smoke, and viruses; the dam-

age predisposes the host to bacterial infections. Different protecting

mechanisms of the respiratory tract contain alveolar macro-

phages, lysozyme in tears and mucus, hairs within the nostril, and the

cough reflex, which prevents aspiration into the lungs.

Lack of the bodily barrier offered by the pores and skin and mucous

membranes predisposes to an infection. Desk 8–1 describes the

organisms that generally trigger infections related to the

lack of these protecting limitations.

The nonspecific safety within the gastrointestinal tract

contains hydrolytic enzymes in saliva, acid within the abdomen, and

varied degradative enzymes and macrophages within the small

gut. The vagina of grownup girls is protected by the low pH

generated by lactobacilli which are a part of the traditional flora.

Extra safety within the gastrointestinal tract and in

the decrease respiratory tract is offered by defensins. These are

extremely positively charged (cationic) peptides that create pores

within the membranes of micro organism, which kills them. Neutrophils

and Paneth cells within the intestinal crypts comprise one sort of

defensin (α-defensins), whereas the respiratory tract produces

completely different defensins referred to as β-defensins. The mechanism by

which defensins distinguish between bacterial membranes and

human cell membranes is incompletely understood, though

there are research that counsel that the differential lipid composi-

tion between microbes and eukaryotes contributes to defensin

specificity. As well as, the invention of microbe-specific lipid

receptors seems to be concerned within the cidal exercise of varied

defensins.

The micro organism of the traditional flora of the pores and skin, nasopharynx,

colon, and vagina occupy these ecologic niches, stopping

pathogens from multiplying in these websites. The significance of

the traditional flora is appreciated within the occasional case when

antimicrobial remedy suppresses these useful organisms,

thereby permitting organisms resembling Clostridium difficile and

Candida albicans to trigger ailments resembling pseudomembranous

colitis and vaginitis, respectively.

Inflammatory Response & Phagocytosis

The presence of international our bodies, resembling micro organism inside the physique,

provokes a protecting inflammatory response (Determine 8–2). This

response is characterised by the scientific findings of redness,

swelling, heat, and ache on the web site of an infection. These indicators

are as a consequence of elevated blood stream, elevated capillary permeabil-

ity, and the escape of fluid and cells into the tissue areas. The

elevated permeability is because of a number of chemical mediators, of

which histamine, prostaglandins, and leukotrienes are the

most vital. Complement parts, C3a and C5a, additionally

contribute to elevated vascular permeability. Bradykinin is an

vital mediator of ache.

Neutrophils and macrophages, each of that are phago-

cytes, are an vital a part of the inflammatory response.

Neutrophils predominate in acute pyogenic infections, whereas

macrophages are extra prevalent in power or granulomatous

infections.

Macrophages carry out two capabilities: they’re phagocytic

they usually produce two vital “proinflammatory” cytokines:

tumor necrosis issue (TNF) and interleukin-1 (IL-1). The syn-

thesis of IL-1 from its inactive precursor is mediated by proteolytic

enzymes (caspases) in a cytoplasmic construction referred to as an inflam-

masome. The significance of the inflammatory response in limit-

ing an infection is emphasised by the power of anti-inflammatory

brokers resembling corticosteroids to decrease resistance to an infection.

Sure proteins, recognized collectively because the acute-phase

response, are additionally produced early in irritation, primarily by

the liver. The very best recognized of those are C-reactive protein and

mannose-binding protein, which bind to the floor of bac-

teria and improve the activation of the choice pathway of

complement (see Chapter 58). C-reactive protein was named

for its capacity to bind with a carbohydrate within the cell wall of

Streptococcus pneumoniae.

Lipopolysaccharide (endotoxin)-binding protein is

one other vital acute-phase protein that’s produced in

response to gram-negative micro organism. Interleukin-6 (IL-6) is the

primary inducer of the acute-phase response and can be a proin-

flammatory cytokine. Macrophages are the principal supply of

IL-6, however many different kinds of cells produce it as effectively. Gamma

interferon, which prompts macrophages and enhances their

microbicidal motion, is produced by activated helper T cells.

Neutrophils and macrophages are interested in the positioning of

an infection by small polypeptides referred to as chemokines (chemotactic

cytokines). Chemokines are produced by tissue cells within the

contaminated space, by native endothelial cells, and by resident neu-

trophils and macrophages. Interleukin-8 is a chemokine that

attracts primarily neutrophils, whereas monocyte chemotactic

protein 1 (MCP-1) and macrophage inflammatory protein

(MIP) are attractants for macrophages and monocytes (see

Chapter 58). The C5a part of complement is one other

vital chemokine (see Chapter 63).

As a part of the inflammatory response, micro organism are engulfed

(phagocytized) by polymorphonuclear neutrophils (PMNs) and

macrophages. PMNs make up roughly 60% of the leuko-

cytes within the blood, and their numbers enhance considerably throughout

an infection (leukocytosis). It ought to be famous, nonetheless, that in

sure bacterial infections resembling typhoid fever, a lower in

the variety of leukocytes (leukopenia) happens. The rise

in PMNs is because of the manufacturing of granulocyte-stimulating

elements (granulocyte colony-stimulating issue [G-CSF] and

granulocyte-macrophage colony-stimulating issue [GM-CSF];

see Chapter 58) by macrophages quickly after an infection.

Word that though each PMNs and macrophages phago-

cytose micro organism, PMNs don’t current antigen to helper

T lymphocytes, whereas macrophages (and dendritic cells)

do (see Chapter 58). Dendritic cells are an important

antigen-presenting cells.

The method of phagocytosis might be divided into three steps:

migration, ingestion, and killing. Migration of PMNs to the

FIGURE 8–3 Opsonization. High: An encapsulated bacterium is

poorly phagocytized by a neutrophil within the absence of both immu-

noglobulin G (IgG) antibody or C3b. Backside: Within the presence of

both IgG antibody or C3b or each, the bacterium is opsonized (i.e., it

is made extra simply phagocytized by the neutrophil).

an infection web site is because of the manufacturing of chemokines, resembling

interleukin-8 and complement part C5a, at that location.

Adhesion of PMNs to the endothelium on the web site of an infection

is mediated first by the interplay of the PMNs with selectin

proteins on the endothelium after which by the interplay of

integrin proteins referred to as “LFA proteins,” situated on the PMN

floor, with intracellular adhesion molecule (ICAM) proteins

on the endothelial cell floor.1

ICAM proteins on the endothelium are elevated by inflam-

matory mediators, resembling IL-1 and TNF (see Chapter 58),

that are produced by macrophages in response to the presence

of micro organism. The rise within the degree of ICAM proteins ensures

that PMNs selectively adhere to the positioning of an infection. Elevated

permeability of capillaries because of histamine, kinins, and

prostaglandins2

permits PMNs emigrate by the capillary

wall to succeed in the micro organism. This migration is known as diapedesis

and takes a number of minutes to happen.

The micro organism are ingested by the invagination of the PMN

cell membrane across the micro organism to type a vacuole

(phagosome). This engulfment is enhanced by the binding of

immunoglobulin G (IgG) antibodies or the C3b part of

complement (each opsonins) to the floor of the micro organism in a

course of referred to as opsonization (Determine 8–3). (The outer cell mem-

branes of each PMNs and macrophages have receptors each for

the Fc portion of IgG and for C3b.)

On the time of engulfment, a brand new metabolic pathway, recognized

because the respiratory burst, is triggered. This leads to the pro-

duction of two microbicidal brokers, the superoxide radical and

hydrogen peroxide. These extremely reactive compounds (usually

referred to as reactive oxygen intermediates) are synthesized by the fol-

lowing reactions

 

 

 

Within the first response, molecular oxygen is decreased by an elec-

tron by NADPH oxidase (also referred to as phagocyte oxidase) to

type the superoxide radical, which is weakly bactericidal. In

the following step, the enzyme superoxide dismutase catalyzes the

formation of hydrogen peroxide from two superoxide radicals.

Hydrogen peroxide is extra poisonous than superoxide however just isn’t

efficient in opposition to catalase-producing organisms resembling staphylo-

cocci. Hydrogen peroxide additionally performs a task within the manufacturing of

hypochlorite, essentially the most highly effective of the microbicidal substances

(see later).

Nitric oxide (NO) is one other vital microbicidal agent.

It’s a reactive nitrogen intermediate that’s synthesized by an

inducible enzyme referred to as nitric oxide synthase in response to

stimulators resembling endotoxin. NO participates in oxidative

killing of ingested microbes phagocytosed by neutrophils and

macrophages. Overproduction of NO contributes to the hypo-

pressure seen in septic shock as a result of it causes vasodilation of

peripheral blood vessels.

The killing of the organism inside the phagosome is

a two-step course of that consists of degranulation adopted

by manufacturing of hypochlorite, which might be essentially the most

vital microbicidal agent. In degranulation, membrane-

sure lysosomal granules, which comprise quite a lot of cytolytic

enzymes, fuse with the phagosome, emptying their contents in

the method, and convert the phagosome right into a construction referred to as

the phagolysosome. Crucial enzyme within the granules

is myeloperoxidase.

It’s right here that the precise killing of the microorganisms happens,

and does so by quite a lot of mechanisms, which fall into two cat-

egories: oxygen-dependent and oxygen-independent. Essentially the most

vital oxygen-dependent mechanism is the manufacturing of

the bactericidal molecule, hypochlorite ion, in line with the

following response:

Cl–

+ H2O2 → ClO–

+ H2O

Myeloperoxidase catalyzes the response between chloride

ion and hydrogen peroxide, which was produced by the

respiratory burst, to provide hypochlorite. Hypochlorite by

itself damages cell partitions however also can react with hydrogen

peroxide to provide singlet oxygen, which damages cells by

reacting with double bonds within the fatty acids of membrane

lipids.

Uncommon people are genetically poor in myeloper-

oxidase, but their protection techniques can kill micro organism, albeit

extra slowly. In these people, the respiratory burst that

produces hydrogen peroxide and superoxide ion appears to

be adequate, however with two caveats: if an organism produces

catalase, hydrogen peroxide can be ineffective, and if an

organism produces superoxide dismutase, superoxide ion

can be ineffective.

The oxygen-independent mechanisms are vital below

anaerobic circumstances. These mechanisms contain lactoferrin,

which chelates iron from the micro organism; lysozyme, which degrades

peptidoglycan within the bacterial cell wall; cationic proteins, which

injury bacterial membranes; and low pH.

Macrophages additionally migrate, engulf, and kill micro organism through the use of

primarily the identical processes as PMNs do, however there are a number of

variations:

(1) Macrophages don’t possess myeloperoxidase and so

can not make hypochlorite ion; nonetheless, they do produce

hydrogen peroxide and superoxide by respiratory burst.

(2) Sure organisms such because the brokers of tuberculosis,

brucellosis, and toxoplasmosis are preferentially ingested by

macrophages fairly than PMNs and should stay viable and

multiply inside these cells; granulomas fashioned throughout these

infections comprise many of those macrophages.

(3) Macrophages secrete plasminogen activator, an enzyme

that converts the proenzyme plasminogen to the lively enzyme

plasmin, which dissolves the fibrin clot.

Lowered Phagocytosis Predisposes to

Bacterial Infections

The significance of phagocytosis as a bunch protection mechanism is

emphasised by the remark that decreased numbers or decreased

perform of phagocytes predisposes to bacterial infections, espe-

cially infections attributable to sure organisms (Desk 8–2):

(1) Repeated infections happen in kids who’ve genetic

defects of their phagocytic processes. Two examples of those

defects are power granulomatous illness, wherein the

phagocyte can not kill the ingested micro organism owing to a defect

in NADPH oxidase and a resultant failure to generate H2O2,

and Chédiak-Higashi syndrome, wherein irregular lysosomal

granules that can’t fuse with the phagosome are fashioned, so

that despite the fact that micro organism are ingested, they survive.

(2) Frequent infections happen in neutropenic sufferers, espe-

cially when the PMN rely drops under 500/μL because of

immunosuppressive medication or irradiation. These infections are

incessantly attributable to opportunistic organisms (i.e., organisms that

hardly ever trigger illness in folks with regular immune techniques).

(3) Splenectomy removes an vital supply of each

phagocytes and immunoglobulins, which predisposes to sepsis

attributable to three encapsulated pyogenic micro organism: S. pneumoniae,

Neisseria meningitidis, and Haemophilus influenzae. S. pneumoniae

causes roughly 50% of episodes of sepsis in splenecto-

mized sufferers. Sufferers with sickle cell anemia and different

hereditary anemias can autoinfarct their spleen, leading to a

lack of splenic perform and a predisposition to sepsis attributable to

these micro organism.

(4) Individuals who have diabetes mellitus, particularly those that

have poor glucose management or episodes of ketoacidosis, have an

elevated variety of infections and extra extreme infections

in contrast with individuals who would not have diabetes. The principle

host protection defect in these sufferers is decreased neutrophil func-

tion, particularly when hyperglycemia and acidosis happen.

Two particular ailments extremely related to diabetes are

malignant otitis externa attributable to Pseudomonas aeruginosa

and mucormycosis attributable to molds belonging to the genera

Mucor and Rhizopus. As well as, there’s an elevated inci-

dence and elevated severity of community-acquired pneu-

monia attributable to micro organism resembling S. pneumoniae and S. aureus

and of urinary tract infections attributable to organisms resembling

Escherichia coli and C. albicans. Candidal vulvovaginitis can be

extra frequent in diabetic sufferers. Diabetic sufferers even have

many foot infections as a result of atherosclerosis compromises the

blood provide and necrosis of tissue happens. Pores and skin infections, such

as ulcers and cellulitis, and gentle tissue infections, resembling necro-

tizing fasciitis, are frequent and may lengthen to the underlying

bone, inflicting osteomyelitis. S. aureus and combined facultative

anaerobic micro organism are the commonest causes.

Fever

An infection causes an increase within the physique temperature that’s attributed

to endogenous pyrogen (IL-1) launched from macrophages.

Fever could also be a protecting response as a result of quite a lot of micro organism

and viruses develop extra slowly at elevated temperatures.

ADAPTIVE (SPECIFIC) IMMUNITY

Adaptive immunity outcomes both from publicity to the organ-

ism (lively immunity) or from receipt of preformed antibody

made in one other host (passive immunity).

Passive adaptive immunity is a short lived safety

in opposition to an organism and is acquired by receiving preformed

antibodies from one other individual or animal. Passive immuniza-

tion happens usually within the type of immunoglobulins handed

by the placenta (IgG) or breast milk (IgA) from mom

to youngster. This safety is essential through the early days

of life when the kid has a decreased capability to mount an lively

response. For instance, immunizing moms with the TDaP

vaccine, which protects in opposition to tetanus, diphtheria, and pertus-

sis, supplies immunity not solely to the mom but in addition to the

toddler because of the passage of IgG from the mom to the toddler.

Passive immunity has the vital benefit that its

protecting talents are current instantly, whereas lively

immunity has a delay of some days to some weeks, relying

on whether or not it’s a major or secondary response. Nevertheless,

passive immunity has the vital drawback that the anti-

physique focus decreases pretty quickly because the proteins are

degraded, and so the safety often lasts for under a month

or two. The administration of preformed antibodies might be life-

saving in sure ailments which are attributable to highly effective exotoxins,

resembling botulism and tetanus. Serum globulins, given intrave-

nously, are a prophylactic measure in sufferers with hypogam-

maglobulinemia or bone marrow transplants. As well as, they

can mitigate the signs of sure ailments resembling hepatitis

attributable to hepatitis A virus, however they seem to have little impact

on bacterial ailments with an invasive type of pathogenesis.

Energetic adaptive immunity is safety primarily based on publicity

to the organism within the type of overt illness, subclinical infec-

tion (i.e., an an infection with out signs), or a vaccine. This

safety has a slower onset however longer period than passive

immunity. The first response often takes 7 to 10 days for

the antibody to turn into detectable. An vital benefit of

lively immunity is that an anamnestic (secondary) response

happens (i.e., there’s a fast response [approximately 3 days] of

massive quantities of antibody to an antigen that the immune sys-

tem has beforehand encountered). Energetic immunity is mediated

by each antibodies (immunoglobulins) and T cells:

(1) Antibodies shield in opposition to organisms by quite a lot of

mechanisms—neutralization of poisons, lysis of micro organism within the

presence of complement, opsonization of micro organism to facilitate

phagocytosis, and interference with adherence of micro organism and

viruses to cell surfaces. If the extent of IgG drops under 400 mg/dL

(regular = 1000–1500 mg/dL), the danger of pyogenic infections

attributable to micro organism resembling staphylococci will increase.

As a result of antibodies, particularly IgG, rise to a protecting degree

slowly (it might take 7 to 10 days after an infection), they’re thought

to not play a significant function in combating the first an infection at

the preliminary web site of an infection (often the pores and skin or mucous mem-

brane), however fairly to guard in opposition to hematogenous dissemina-

tion of the organism to distant websites within the physique and in opposition to a

second an infection by that organism at some future time.

(2) T cells mediate quite a lot of reactions, together with cytotoxic

destruction of virus-infected cells and micro organism, activation of

macrophages, and delayed hypersensitivity. T cells, particularly

Th-1 cells (see Chapter 58) and macrophages, are the primary host

protection in opposition to mycobacteria resembling M. tuberculosis and sys-

temic fungi resembling Histoplasma and Coccidioides. T cells additionally

assist B cells to provide antibody in opposition to many, however not all,

antigens.

Desk 8–3 describes the important host protection mechanisms

in opposition to micro organism. These mechanisms embody each humoral

immunity in opposition to pyogenic micro organism and exotoxins and cell-

mediated immunity in opposition to a number of intracellular micro organism.

 

FAILURE OF HOST DEFENSES

PREDISPOSES TO INFECTIONS

The frequency or severity of infections is elevated when sure

predisposing circumstances exist. These predisposing circumstances

fall into two primary classes: sufferers are immunocompromised

or sufferers have international our bodies resembling indwelling catheters

or prosthetic units. Overseas our bodies predispose as a result of host

defenses don’t function effectively of their presence. Desk 8–4

describes the predisposing circumstances and the commonest

organisms inflicting infections when these predisposing condi-

tions are current.

Sure ailments and anatomic abnormalities additionally predispose

to infections. For instance, sufferers with diabetes usually have

S. aureus infections, maybe for 2 causes: these sufferers have

intensive atherosclerosis, which causes relative anoxia to tissue,

they usually have a defect in neutrophil perform. Sufferers with

sickle cell anemia usually have Salmonella osteomyelitis, most likely

as a result of the abnormally formed cells occlude the small capil-

laries within the bone. This traps the Salmonella inside the bone,

rising the danger of osteomyelitis.

Sufferers with sure congenital cardiac defects or rheumatic

valvular injury are predisposed to endocarditis attributable to viri-

dans streptococci. Neutrophils have problem in penetrating the

vegetations fashioned on the valves in endocarditis. Sufferers with

an aortic aneurysm are susceptible to vascular infections attributable to

Salmonella species.

Sufferers with decreased host defenses usually have a muted

response to an infection (e.g., a low-grade [or no] fever and a gentle

[or absent] inflammatory response). For that reason, a excessive

index of suspicion concerning the presence of an infection should

be current when evaluating sufferers who’re immunocom-

promised, particularly those that are deliberately immunosup-

pressed, resembling transplant recipients.