Immunodeficiency: Understanding the Complexities of a Weakened Immune System and its Affect on Well being and Properly-being

Immunodeficiency: Understanding the Complexities of a Weakened Immune System and its Affect on Well being and Properly-being

 

INTRODUCTION

Immunodeficiency can happen in any of the 4 main compo-

nents of the immune system: (1) B cells (antibody), (2) T cells,

(3) complement, and (4) phagocytes. In a affected person with a historical past

of infections which might be unusually frequent, unusually extreme,

or attributable to uncommon organisms, the sample of those infec-

tions can point out which element(s) of the immune system

is perhaps faulty. Most immunodeficiencies are acquired, and

these are continuously attributable to immunosuppressive medica-

tions, transplantation, and/or ailments that suppress immunity.

Though they’re much less frequent, congenital immunodeficiencies

(Desk 68–1) are vital to know as a result of (1) the pat-

terns of infections which might be seen educate us how numerous immune

parts are presupposed to operate usually and (2) current

technological advances have allowed us to higher diagnose and

deal with these ailments, stopping the infectious issues.

CONGENITAL IMMUNODEFICIENCIES

T-Cell Deficiencies

Congenital T-cell deficiencies are typically probably the most extreme and

simply acknowledged immunodeficiency. As a result of T cells are central

to so many facets of immune responses, together with antiviral

immunity, maturation of B cells and antibody, and the activa-

tion of macrophages, their absence ends in a broad vary of

uncommon opportunistic infections (i.e., viruses, micro organism, fungi,

and protozoa which might be not often seen in wholesome hosts). These dis-

eases typically current inside the first 6 to 12 months of life when

maternal antibody is waning. They’re additionally normally related

with some extent of B-cell deficiency. Extreme T-cell deficiency

shouldn’t be appropriate with life; with no hematopoietic stem cell

transplant, these kids not often reside previous the age of two years,

and these transplants are solely attainable if the prognosis is made

earlier than the onset of extreme infectious issues. New child

screening for T-cell receptor excision circles (TRECs) has

vastly elevated the effectivity of prognosis of those ailments

(see Chapter 59).

(1) Wiskott-Aldrich syndrome—Recurrent pyogenic infec-

tions, eczema, and low platelets characterize this syndrome.

The signs sometimes seem through the first yr of life. It

is an X-linked illness attributable to mutations within the WASp gene,

resulting in a defect in actin filament meeting that’s vital

for T cells to reply to antigen presentation and for B cells to

be activated by alerts from the B-cell receptor. These sufferers

are subsequently unable to mount an IgM response to the capsular

polysaccharides of micro organism, reminiscent of pneumococci, whereas IgA

and IgE ranges might be elevated.

(2) Ataxia-telangiectasia—On this illness, ataxia (stagger-

ing) and telangiectasia (enlarged small blood vessels of the

conjunctivas and pores and skin) happen. About two-thirds of sufferers have

lymphopenia and low immunoglobulins, significantly IgA,

which leads to recurrent pyogenic higher respiratory infec-

tions that seem by 2 years of age. It’s an autosomal recessive

illness attributable to mutations within the genes that encode DNA

restore enzymes. Along with the lymphopenia, these sufferers

continuously develop leukemia, lymphoma, or different cancers.

(3) Thymic aplasia (DiGeorge’s syndrome)—On this dis-

ease, each the thymus and the parathyroids fail to develop

correctly because of a defect within the third and fourth

pharyngeal pouches. (In full DiGeorge syndrome, the

thymus is totally absent, however that is fairly uncommon. Extra typically,

the thymus is just malformed or small.) A typical present-

ing symptom is tetany on account of hypocalcemia attributable to hypo-

parathyroidism. Aortic arch malformations and cleft palate can

even be seen in these sufferers. It’s normally attributable to a spontane-

ous deletion in chromosome 22 throughout early improvement,

though uncommon instances are inherited genetically.

Extreme viral, fungal, or protozoal infections happen in affected

infants early in life because of absence of the thymus, the place

T-cell precursors recombine their receptors and mature to

turn into T cells (see Chapter 59). Pneumonia attributable to Pneu-

mocystis jiroveci and thrush attributable to Candida albicans are two

frequent infections in these sufferers. Antibody manufacturing could

be decreased or regular. If decreased, extreme pyogenic bacterial

infections can happen.

This illness is uncommon in that it isn’t attributable to a defect in

the bone marrow precursor cells. The T-cell precursors them-

selves are regular, and so performing a thymus transplant into

these sufferers can largely right the defect by permitting the

affected person’s personal T-cell precursors to mature.

(4) Cytokine signaling defects—Sufferers with defects in

particular cytokines or their receptors have elevated susceptibil-

ity to particular organisms. For instance, persistent mucocutane-

ous candidiasis is an an infection of the pores and skin and mucous

membranes with C. albicans, which in immunocompetent

people is a nonpathogenic member of the traditional flora. In

uncommon households with heritable mucocutaneous candidiasis, the

total T-cell and B-cell ranges and features are regular besides

that there’s deficiency particularly of interleukin (IL)-17 or the

IL-17 receptor.

In distinction, defects in IL-12, gamma interferon (IFN-γ), or

the receptors for these cytokines, end in recurrent or extreme

infections with mycobacteria and Salmonella species. IL-12

usually helps to distinguish naïve CD4-positive T cells into

Th-1 cells, which make the IFN-γ that’s required to activate the

macrophages that restrict these infections (see Chapter 60). A com-

mon presentation of IL-12 or IFN-γ deficiency is a baby with

disseminated an infection with bacillus Calmette-Guérin (BCG),

the attenuated Mycobacterium pressure within the BCG vaccine that’s

given in lots of international locations to stop extreme tuberculosis illness.

Deficiency within the gene encoding the transcription issue

STAT3 causes defects in IL-23, IL-6, and IL-21 signaling. STAT3

is crucial for the differentiation of Th-17 cells however can also be

vital in B-cell class switching and neutrophil activation.

This results in excessive ranges of IgE and impaired neutrophil migra-

tion to barrier surfaces, inflicting recurrent staphylococcal pores and skin

infections. These sufferers may have eosinophilia, eczema,

and skeletal defects. The autosomal dominant kind is referred

to as Job’s syndrome or hyper-IgE syndrome.

Mixed T- & B-Cell Deficiency

An remoted T-lymphocyte deficiency is a life-threatening con-

dition, however much more devastating are deficiencies attributable to

defects in all lymphocyte improvement, which causes extreme

mixed immunodeficiency (SCID). On this illness, recur-

hire infections attributable to micro organism, viruses, fungi, and protozoa

happen in early infancy (3 months of age) as a result of each B cells

and T cells are faulty. In some kids, the B and T cells are

fully absent; in others, the variety of cells is regular however

they don’t operate correctly. Immunoglobulin ranges are very

low, and tonsils and lymph nodes are absent. Be aware that innate

immunity shouldn’t be straight affected, however with out adaptive immu-

nity, the innate immune system is unable to clear infections.

Pneumocystis pneumonia is the commonest presenting

an infection in these infants. Infections attributable to C. albicans and

viruses reminiscent of varicella-zoster virus, cytomegalovirus, and

respiratory syncytial virus are frequent and infrequently deadly.

It is a group of inherited ailments (see beneath), every of

which is because of a defect within the differentiation of lymphocytes.

The X-linked kind is the commonest, however many autosomal

kinds additionally happen.

(1) X-linked SCID is attributable to a defect in a single protein

chain of the IL-2 receptor, a series that can also be shared with the

receptors for IL-7 and several other different cytokines.

Autosomal kinds embody the next mutations:

(2) The gene encoding a tyrosine kinase known as ZAP-70 that

performs a task in sign transduction in T cells.

(3) The gene encoding a unique kinase known as Janus

kinase 3, which transmits activation and survival alerts from

cell floor receptors.

(4) The RAG-1 or RAG-2 genes that encode the recombinase

enzymes that catalyze the recombination of the DNA required

to generate the T-cell antigen receptor and the IgM monomer

on the B cell that acts because the antigen receptor.

(5) Deficiency of adenosine deaminase (ADA) and purine

nucleoside phosphorylase (PNP), enzymes that recycle nucle-

otides for DNA synthesis, which reduces the flexibility of B-cell and

T-cell precursors to divide and survive within the bone marrow.

(6) Faulty class I or class II main histocompatibility

advanced (MHC) proteins, inflicting lack of ability to show antigens

to T cells (additionally known as naked lymphocyte syndrome).

As a result of immunity is so profoundly depressed, kids with

SCID have to be strictly remoted from doubtlessly dangerous micro-

organisms. Dwell, attenuated viral vaccines shouldn’t be given.

Hematopoietic stem cell transplantation could restore immu-

nity, and since infants with SCID don’t reject allografts,

these transplants require minimal immunosuppressive medicine

to engraft.

In sufferers with ADA deficiency, enzyme substitute ther-

apy can increase lymphocyte numbers and cut back the quantity

and severity of infections. A number of sufferers with ADA deficiency

have benefited from gene remedy, putting a brand new practical

enzyme of their hematopoietic stem cells.

B-Cell Deficiencies

Congenital deficiencies within the quantity or operate of B cells

trigger low or absent antibody ranges. Just like the T-cell and com-

bined deficiencies, sufferers with these deficiencies are protected

from infections by maternal antibody till the age of 6 to

12 months, at which level they start to have recurrent infec-

tions. Nevertheless, not like the “opportunistic” infections described

earlier, recurrent bacterial infections and impaired responses

to vaccines are normally the presenting discovering in sufferers with

low antibody ranges. Their infections are sometimes within the oropharynx

and respiratory tract, together with sinusitis, otitis, and pneumo-

nia, as these are the websites protected by antibody. However antibody

deficiencies additionally predispose sufferers to sure viral infections,

infections of the gastrointestinal tract, and bacteremia from

encapsulated organisms.

(1) X-linked hypogammaglobulinemia (Bruton’s agamm-

aglobulinemia)—Boys with this illness have low ranges of all

immunoglobulins (IgG, IgA, IgM, IgD, and IgE) and a digital

absence of B cells; feminine carriers are immunologically nor-

mal. Pre-B cells are current, however they fail to distinguish into

mature B cells. This failure is attributable to a mutation within the

gene encoding a tyrosine kinase that is a crucial sign

transduction protein. Clinically, recurrent pyogenic bacterial

infections (e.g., otitis media, sinusitis, and pneumonia triggered

by Streptococcus pneumoniae and Haemophilus influenzae)

happen in infants at about 6 months of age, when maternal anti-

physique is not current in adequate quantity to be protecting.

Remedy with pooled gamma globulin reduces the quantity

of infections.

(2) IgA deficiency—That is the commonest antibody

class deficiency; IgG and IgM deficiencies are rarer. Sufferers

with a deficiency of IgA can have recurrent sinus and lung

infections. Nevertheless, with time, the infections turn into much less and

much less frequent, and a few people with IgA deficiency don’t

have frequent infections. That is seemingly as a result of their IgG and

IgM ranges confer safety that compensates for the lack of

IgA. The reason for IgA deficiency could also be a failure of heavy chain

gene switching. Sufferers with a deficiency of IgA shouldn’t be

handled with gamma globulin preparations, as a result of the IgA in

the infusion might be immunogenic in these sufferers, i.e., they will

kind antibodies towards the overseas IgA.

Sufferers with selective IgM deficiency or deficiency of 1 or

extra of the IgG subclasses even have recurrent sinopulmonary

infections attributable to pyogenic micro organism reminiscent of S. pneumoniae,

H. influenzae, or Staphylococcus aureus.

(3) Hyper-IgM syndrome—On this syndrome, extreme, recur-

hire pyogenic bacterial infections resembling these seen in

X-linked hypogammaglobulinemia start early in life. Sufferers

have a excessive focus of IgM however little or no IgG, IgA, and

IgE. However not like the X-linked agammaglobulinemia sufferers,

these sufferers have regular numbers of B cells. As a substitute, the

deficiency is within the gene encoding CD40 ligand (CD40L), which

CD4-positive T cells specific to bind and activate different cells

by means of CD40. CD40L is without doubt one of the essential parts of T-cell

assist. T follicular helper (Tfh) cells from these sufferers lack

CD40L, and their failure to correctly work together with B-cell CD40

ends in an lack of ability of the B cell to change from the manufacturing

of IgM to the opposite courses of antibodies. Remedy with pooled

gamma globulin ends in fewer infections.

(4) Widespread variable immunodeficiency (CVID)—This

time period really includes a heterogeneous group of ailments,

most of that are idiopathic. Like different antibody deficiencies,

sufferers with CVID current with low IgG ranges and recurrent

infections attributable to pyogenic micro organism (e.g., sinusitis and

pneumonia attributable to pyogenic micro organism reminiscent of S. pneumoniae

and H. influenzae). Nevertheless, the infections are typically milder

and should even start to happen later in life, between the ages of

15 and 35 years. (This has led to hypothesis that some types of

idiopathic CVID are literally acquired moderately than congenital.)

Like hyper-IgM syndrome (described earlier), the identified

causes of CVID are sometimes practical defects in helper T cells

moderately than in B cells. The variety of B cells is normally regular,

however their means to synthesize IgG (and different immunoglobulins)

is vastly decreased. Intravenous gamma globulin given month-to-month

reduces the variety of infections.

Complement Deficiencies

The complement system is a crucial initiator of many

inflammatory processes. It performs a key position in complement-

dependent cytotoxicity (CDC) and in immune advanced

deposition (kind III hypersensitivity) reactions seen in lots of

autoimmune and inflammatory issues. Chapter 63 describes

a number of circumstances during which complement is overactivated,

together with hereditary angioedema, attributable to C1 inhibitor defi-

ciency, and paroxysmal nocturnal hemoglobinuria, attributable to

a failure of decay-accelerating issue to be displayed on the cell

membrane.

In host protection, many parts of the complement cas-

cade play overlapping roles with different immune parts

(e.g., antibody). Which means, though ailments of inherited

complement deficiencies do exist, the infectious issues

in these sufferers are comparatively uncommon.

Sufferers with deficiencies in C1, C3, or C5 or the compo-

nents recruited later within the cascade, C6, C7, or C8, have an

elevated susceptibility to bacterial infections. Sufferers with C3

deficiency are significantly prone to sepsis with pyogenic

micro organism reminiscent of S. aureus. These with decreased ranges of C6,

C7, or C8, which kind the membrane assault advanced (see

Chapter 63), are particularly vulnerable to bacteremia with Neisseria

meningitidis or Neisseria gonorrhoeae.

Phagocyte Deficiencies

(1) Power granulomatous illness (CGD)—Sufferers with

this illness are prone to opportunistic infections with cer-

tain micro organism and fungi (e.g., S. aureus); enteric gram-negative

rods, particularly Serratia and Burkholderia; and Aspergillus

fumigatus. CGD is because of a defect within the intracellular micro-

bicidal exercise of phagocytes because of a scarcity of NADPH

oxidase exercise (or related enzymes). A lot much less hydrogen

peroxide and superoxides are produced (i.e., no oxidative burst

happens), and the organisms, though ingested, should not killed

as effectively. Even with this deficiency, a phagocyte can use

hydrogen peroxide produced by the microbe itself to generate

poisonous hypochlorite, however CGD sufferers have a specific sus-

ceptibility to infections with catalase-positive micro organism, reminiscent of

staphylococci, as a result of the microbial catalase additional degrades

what little peroxide there may be to water and oxygen. (Infections

with catalase-negative micro organism, reminiscent of streptococci, and viral,

mycobacterial, and protozoal infections are of much less concern in

CGD sufferers than infections attributable to catalase-positive bac-

teria and fungi.) B-cell and T-cell features are normally regular.

In 60% to 80% of instances, that is an X-linked illness that seems

by the age of two years. (Within the remaining sufferers, the illness is

autosomal.)

Within the laboratory, prognosis might be confirmed by the nitro

blue tetrazolium (NBT) dye discount check or by the dichlo-

rofluorescein (DCF) check. Within the NBT check, regular neutro-

phils will flip the dye a blue coloration, whereas the neutrophils

of a affected person with CGD fail to provide the blue coloration. Within the

DCF check, cells that oxidize the DCF are detected by stream

cytometry.

Immediate, aggressive remedy of an infection with the appropri-

ate antibiotics is vital. Chemoprophylaxis utilizing antibac-

terials can cut back the variety of infections. Gamma interferon

remedy considerably reduces the frequency of recurrent

infections, most likely as a result of it will increase phagocytosis by

macrophages.

The title persistent granulomatous illness arises from the

widespread granulomas seen in these sufferers, even within the

absence of clinically obvious an infection. These granulomas

can turn into giant sufficient to trigger obstruction of the stom-

ach, esophagus, or bladder. The reason for these granulomas is

unknown.

(2) Chédiak-Higashi syndrome—On this autosomal reces-

sive illness, recurrent pyogenic infections, triggered primarily by

staphylococci and streptococci, happen. That is as a result of failure

of the lysosomes of neutrophils to fuse with phagosomes. The

degradative enzymes within the lysosomes are, subsequently, not avail-

in a position to kill the ingested organisms. Giant granular inclusions

composed of irregular lysosomes are seen. As well as, the

neutrophils don’t operate appropriately throughout chemotaxis as a

results of defective microtubules. The mutant gene on this illness

encodes a cytoplasmic protein concerned in protein transport.

Peroxide and superoxide formation is regular, as are B-cell and

T-cell features. Remedy includes antimicrobial medicine. There

isn’t any helpful remedy for the phagocyte defect.

(3) Leukocyte adhesion deficiency syndrome—Sufferers

with this syndrome have extreme pyogenic infections early in

life as a result of they’ve faulty adhesion (LFA-1) proteins

on the floor of their phagocytes. That is an autosomal

recessive illness in which there’s a mutation within the gene

encoding the β chain of an integrin that mediates adhesion.

Because of this, neutrophils adhere poorly to endothelial cell sur-

faces and can’t exit the blood circulation (see Determine 58–4).

Accordingly, though they’re immunosuppressed, these

sufferers typically have extraordinarily excessive numbers of leukocytes in

the blood.

(4) Cyclic neutropenia—On this autosomal dominant dis-

ease, sufferers have a really low neutrophil rely (< 200/μL) for

3 to six days of a 21-day cycle. Throughout the neutropenic stage,

sufferers are prone to life-threatening bacterial infections,

however when neutrophil counts are regular, sufferers should not sus-

ceptible. Mutations within the gene encoding neutrophil elastase

have been recognized in these sufferers, however it’s unclear how

these contribute to the cyclic nature of the illness. It’s

hypothesized that irregular manufacturing of granulocyte colony-

stimulating issue could play a task within the cyclic facet of the

illness.

Sample-Recognition Receptor Deficiency

Mutations within the genes encoding the sample recognition

receptors (PRRs) on the floor of and inside the cells of

the innate immune system end in susceptibility to extreme

infections (Desk 68–2). For extra data on PRRs, see

Chapter 58.

(1) Receptors on the floor of innate immune cells—

Deficiency of Toll-like receptor-5 (TLR-5) ends in a failure

to acknowledge flagellin on micro organism and a marked susceptibil-

ity to Legionella infections. This deficiency is sort of com-

mon. Deficiency of mannose-binding lectin (MBL) can also be

frequent. It ends in a failure to activate complement

by means of the lectin pathway (see Chapter 63). Nevertheless, there

are redundant pathways of complement activation, and it’s

not clear that this really presents a clinically important

immunodeficiency.

(2) Receptors inside innate immune cells—NOD receptors

within the cytoplasm acknowledge the peptidoglycan of gram-positive

and gram-negative micro organism. Varied mutations of NOD-2 have

been related to Crohn’s illness, presumably ensuing

from defects in intestine barrier immunity and small quantities of

micro organism in a position to invade the intestinal wall. RIG helicase recep-

tors acknowledge viral double-stranded RNAs synthesized throughout

replication within the cytoplasm. Deficiency of those receptors

ends in a decreased interferon response to numerous viruses (i.e.,

influenza virus).

ACQUIRED IMMUNODEFICIENCIES

Earlier chapters have addressed a number of the immunosup-

pressive medicines, reminiscent of corticosteroids, that may trigger

acquired immunodeficiency (see Tables 62–2 and 66–3).

Cushing syndrome, which might be attributable to extreme publicity

to exogenous or endogenous corticosteroids, is related to

immunosuppression. As mentioned in Chapters 57 and 66, ageing

and being pregnant are related to comparatively depressed immu-

nity. Lastly, sure cancers, significantly the malignancies of

hematopoietic cells (e.g., leukemia, lymphoma, and myeloma),

may cause immunosuppression when extreme proliferation of

the malignant cells “crowds out” the leukocyte progenitor cells

within the bone marrow.

T-CELL DEFICIENCIES

(1) Acquired immunodeficiency syndrome—Sufferers with

acquired immunodeficiency syndrome (AIDS) current with

opportunistic infections attributable to sure micro organism, viruses,

fungi, and protozoa (e.g., Mycobacterium avium-intracellulare,

herpesviruses, C. albicans, P. jiroveci, and Cryptosporidium).

This is because of decreased helper T-cell numbers attributable to infec-

tion with the retrovirus human immunodeficiency virus

(HIV; see Chapter 45). This virus particularly infects and kills

cells bearing the CD4 floor protein. The response to particular

immunizations is poor; that is attributed to the lack of helper

T-cell exercise. AIDS sufferers even have a excessive incidence of

tumors reminiscent of lymphomas, which can be the results of a failure

of immune surveillance. See Chapter 45 for data on

remedy and prevention.

(2) Measles—Sufferers with measles have a transient sup-

pression of delayed hypersensitivity as manifested by a loss

of reactivity to purified protein by-product (PPD), which is

used within the pores and skin check for latent tuberculosis. Tuberculosis can

really reactivate in these sufferers. Regardless of the depressed

T-cell operate on this illness, immunoglobulins are

regular.

B-Cell Deficiencies

(1) Malnutrition—Extreme malnutrition can cut back the sup-

ply of amino acids and thereby cut back the synthesis of IgG. This

predisposes to an infection by pyogenic micro organism.

(2) Asplenia—Sufferers sometimes have to have their

spleen eliminated by means of a surgical splenectomy, both as a result of

of a traumatic splenic rupture, a malignancy, or an autoimmune

illness reminiscent of immune thrombocytopenic purpura. Some

sufferers with regular splenic tissue nonetheless develop “func-

tional asplenia,” as happens in sufferers with sickle cell illness

that suffer quite a few splenic infarcts. With out a spleen, anti-

physique responses to new antigens are typically suppressed,

though antibodies to beforehand encountered antigens are gen-

erally intact. It’s because the long-lived plasma cells respon-

sible for circulating antibodies normally go away the spleen and

reside within the bone marrow.

Complement Deficiencies

(1) Liver failure—Liver failure attributable to alcoholic cirrhosis

or by persistent hepatitis B or hepatitis C can cut back the synthesis

of complement proteins by the liver to a stage that permits extreme

pyogenic infections to happen.

(2) Malnutrition—Extreme malnutrition can cut back the sup-

ply of amino acids and thereby cut back the synthesis of comple-

ment proteins by the liver. This predisposes to an infection by

pyogenic micro organism.

Phagocyte Deficiencies

(1) Neutropenia—Sufferers with neutropenia (low circu-

lating neutrophils) current with extreme infections attributable to

pyogenic micro organism, reminiscent of S. aureus and S. pneumoniae and

enteric gram-negative rods. This happens as a result of neutrophils are

a significant element of the immune barrier within the pores and skin, orophar-

ynx, and gastrointestinal tract. Neutrophil counts beneath 500/μL

predispose to those infections. Widespread causes of neutropenia

embody cytotoxic medicine, reminiscent of these utilized in most cancers chemo-

remedy; leukemia, during which the bone marrow is “crowded out”

by leukemic cells; and autoimmune destruction of the neu-

trophils. Ciprofloxacin is used to attempt to stop infections in

neutropenic sufferers.