1. THE IMMUNE SYSTEM
By: Dodge Churchill P. Toledo, RN
Dorie Ann R. Daza, RN
The Normal Immune Response
INNATE IMMUNITY
• (also called natural, or native, immunity) refers to defense mechanisms that are present
even before infection and that have evolved to specifically recognize microbes and protect
individuals against infections.
• Innate immunity is the first line of defense, because it is always ready to prevent and
eradicate infections.
The two most important cellular reactions of innate immunity are:
• inflammation, the process in which phagocytic leukocytes are recruited and activated to
kill microbes
• anti-viral defense, mediated by dendritic cells and NK cells.
ADAPTIVE IMMUNITY
• (also called acquired, or specific, immunity) consists of mechanisms that are stimulated by
(“adapt to”) microbes and are capable of recognizing microbial and nonmicrobial
substances.
• Adaptive immunity develops later, after exposure to microbes, and is even more powerful
than innate immunity in combating infections. By convention, the term “immune response”
refers to adaptive immunity.
There are two types of adaptive immunity:
• humoral immunity, which protects against extracellular microbes and their toxins.
Humoral immunity is mediated by B (bone marrow–derived) lymphocytes and their secreted
products, antibodies (also called immunoglobulins, Ig)
• cell-mediated (or cellular) immunity, which is responsible for defense against
intracellular microbes. Cellular immunity is mediated by T (thymus-derived) lymphocytes.
Both classes of lymphocytes express highly specific receptors for a wide variety of
substances, called antigens.
Hypersensitivity
• implying an excessive response to antigen
There are several important general features of hypersensitivity disorders.
• Both exogenous and endogenous antigens may elicit hypersensitivity reactions
• The development of hypersensitivity diseases (both allergic and autoimmune disorders) is
often associated with the inheritance of particular susceptibility genes.
2. • Hypersensitivity reflects an imbalance between the effector mechanisms of immune
responses and the control mechanisms that serve to normally limit such responses
The main types of hypersensitivity reactions are the following:
• Immediate hypersensitivity (type I hypersensitivity), the immune response is mediated
by TH2 cells, IgE antibodies, and mast cells, and results in the release of mediators that act
on vessels and smooth muscle and of pro-inflammatory cytokines that recruit inflammatory
cells.These reactions are often called allergy.
Immediate (type I) hypersensitivity is a complex disorder resulting from an IgE-mediated
triggering of mast cells and subsequent accumulation of inflammatory cells at sites of
antigen deposition. These events are regulated mainly by the induction of TH2 helper T
cells that stimulate production of IgE (which promotes mast cell activation), cause
accumulation of inflammatory cells (particularly eosinophils), and trigger secretion of
mucus. The clinical features result from release of mast cell mediators as well as the
eosinophil-rich inflammation.
• Antibody-mediated disorders (type II hypersensitivity), secreted IgG and IgM
antibodies participate directly in injury to cells by promoting their phagocytosis or lysis and
in injury to tissues by inducing inflammation. Antibodies may also interfere with cellular
functions and cause disease without tissue injury.
• Immune complex–mediated disorders (type III hypersensitivity), IgG and IgM
antibodies bind antigens usually in the circulation, and the antigen-antibody complexes
deposit in tissues and induce inflammation. The leukocytes that are recruited (neutrophils
and monocytes) produce tissue damage by release of lysosomal enzymes and generation
of toxic free radicals.
• Cell-mediated immune disorders (type IV hypersensitivity), sensitized T lymphocytes
(TH1 and TH17 cells and CTLs) are the cause of the cellular and tissue injury. TH2 cells
induce lesions that are part of immediate hypersensitivity reactions, and are not considered
a form of type IV hypersensitivity
Autoimmune diseases
SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)
• SLE is the prototype of a multisystem disease of autoimmune origin, characterized by a vast array
of autoantibodies, particularly antinuclear antibodies (ANAs).
Etiology and Pathogenesis of SLE
The cause of SLE remains unknown, but the existence in these patients of a seemingly limitless
number of antibodies against self-constituents indicates that the fundamental defect in SLE is a
failure of the mechanisms that maintain self-tolerance. As is true of most autoimmune diseases, both
genetic and environmental factors play a role in the pathogenesis of SLE.
To summarize, SLE is a complex disorder of multifactorial origin resulting from interactions among
genetic, immunological, and environmental factors that act in concert to cause activation of helper T
cells and B cells and result in the production of several species of pathogenic autoantibodies.
Morphology. The morphologic changes in SLE are extremely variable, as are the clinical
manifestations and course of disease. The constellation of clinical, serologic, and morphologic
changes is essential for diagnosis. The most characteristic lesions result from immune complexes
depositing in blood vessels, kidneys, connective tissue, and skin.
An acute necrotizing vasculitis involving capillaries, small arteries and arterioles may be present in
any tissue.The arteritis is characterized by fibrinoid deposits in the vessel walls. In chronic stages,
vessels undergo fibrous thickening with luminal narrowing.
3. Kidney. Lupus nephritis affects up to 50% of SLE patients. The principal mechanism of injury is
immune complex deposition in the glomeruli, tubular or peritubular capillary basement membranes, or
larger blood vessels. Other injuries may include thrombi in glomerular capillaries, arterioles, or
arteries, often associated with antiphospholipid antibodies.
All of the glomerular lesions described below are the result of deposition of immune complexes that
are regularly present in the mesangium or along the entire basement membrane and sometimes
throughout the glomerulus. The immune complexes consist of DNA and anti-DNA antibodies, but
other antigens such as histones have also been implicated. Both in situ formation and deposition of
preformed circulating immune complexes may contribute to the injury, but the reason for the wide
spectrum of histopathologic lesions (and clinical manifestations) in lupus nephritis patients remains
uncertain.
A morphologic classification of lupus nephritis has proven to be clinically useful. Five patterns are
recognized: minimal mesangial (class I); mesangial proliferative (class II); focal proliferative (class III);
diffuse proliferative (class IV); and membranous (class V). None of these patterns is specific for
lupus.
Mesangial lupus glomerulonephritis is seen in 10% to 25% of patients and is characterized by
mesangial cell proliferation and immune complex deposition without involvement of glomerular
capillaries. There is no or slight (class I) to moderate (class II) increase in both mesangial matrix and
number of mesangial cells. Granular mesangial deposits of immunoglobulin and complement
are always present. Classes III to V nephritis, described below, are usually superimposed on some
degree of mesangial changes.
Focal proliferative glomerulonephritis (class III) is seen in 20% to 35% of patients, and is defined
by fewer than 50% involvement of all glomeruli. The lesions may be segmental (affecting only a
portion of the glomerulus) or global (involving the entire glomerulus). Affected glomeruli may exhibit
crescent formation, fibrinoid necrosis, proliferation of endothelial and mesangial cells, infiltrating
leukocytes, and eosinophilic deposits or intracapillary thrombi , which often correlate with hematuria
and proteinuria. Some patients may progress to diffuse proliferative glomerulonephritis. The active (or
proliferative) inflammatory lesions can heal completely or lead to chronic global or segmental
glomerular scarring.
Diffuse proliferative glomerulonephritis (class IV) is the most severe form of lupus nephritis,
occurring in 35% to 60% of patients. Pathologic glomerular changes may be identical to focal (class
III) lupus nephritis, including proliferation of endothelial, mesangial and, sometimes, epithelial cells,
with the latter producing cellular crescents that fill Bowman's space. The entire glomerulus is
frequently affected but segmental lesions also may occur. Both acutely injured and chronically
scarred glomeruli in focal or diffuse lupus nephritis are qualitatively indistinguishable from one
another; the distinction is based solely on the percentage of glomerular involvement (<50% for class
III vs >50% for class IV). Patients with diffuse glomerulonephritis are usually symptomatic, showing
hematuria as well as proteinuria. Hypertension and mild to severe renal insufficiency are also
common.
Membranous glomerulonephritis (class V) is characterized by diffuse thickening of the capillary
walls, which is similar to idiopathic membranous glomerulonephritis. This lesion is seen in 10% to
15% of lupus nephritis patients, is usually accompanied by severe proteinuria or nephrotic syndrome,
and may occur concurrently with focal or diffuse lupus nephritis.
Granular deposits of antibody and complement can be detected by immunofluorescence. Electron
microscopy demonstrates electron-dense deposits that represent immune complexes in mesangial,
intramembranous, subepithelial, or subendothelial locations. All classes show variable amounts of
mesangial deposits. In membranous lupus nephritis, the deposits are predominantly subepithelial
(between the basement membrane and visceral epithelial cells). Subendothelial deposits (between
the endothelium and the basement membrane) are seen in the proliferative types (classes III and IV)
but may be encountered rarely in class I, II, and V lupus nephritis. When prominent, subendothelial
deposits create a homogeneous thickening of the capillary wall, which are seen by light microscopy
as a “wire-loop” lesion. Such wire loops are often found in both focal and diffuse proliferative (class
III or IV) lupus nephritis, which reflects active disease.
4. Changes in the interstitium and tubules are frequently present in lupus nephritis patients. Rarely,
tubulointerstitial lesions may be the dominant abnormality. Discrete immune complexes similar to
those in glomeruli are present in the tubular or peritubular capillary basement membranes in many
lupus nephritis patients.
Skin. Characteristic erythema affects the facial butterfly (malar) area (bridge of the nose and cheeks)
in approximately 50% of patients, but a similar rash may also be seen on the extremities and trunk.
Urticaria, bullae, maculopapular lesions, and ulcerations also occur. Exposure to sunlight incites or
accentuates the erythema. Histologically the involved areas show vacuolar degeneration of the
basal layer of the epidermis. In the dermis, there is variable edema and perivascular inflammation.
Vasculitis with fibrinoid necrosis may be prominent. Immunofluorescence microscopy shows
deposition of immunoglobulin and complement along the dermoepidermal junction, which may also
be present in uninvolved skin. This finding is not diagnostic of SLE and is sometimes seen in
scleroderma or dermatomyositis.
Joints. Joint involvement is typically a nonerosive synovitis with little deformity, which contrasts with
rheumatoid arthritis.
Central Nervous System. The pathologic basis of central nervous system symptoms is not entirely
clear, but antibodies against a synaptic membrane protein have been implicated. Neuropsychiatric
symptoms of SLE have often been ascribed to acute vasculitis, but in histologic studies of the
nervous system in such patients significant vasculitis is rarely present. Instead, noninflammatory
occlusion of small vessels by intimal proliferation is sometimes noted, which may be due to
endothelial damage by antiphospholipid antibodies.
Pericarditis and Other Serosal Cavity Involvement. Inflammation of the serosal lining membranes
may be acute, subacute, or chronic. During the acute phases, the mesothelial surfaces are
sometimes covered with fibrinous exudate. Later they become thickened, opaque, and coated with a
shaggy fibrous tissue that may lead to partial or total obliteration of the serosal cavity.
Cardiovascular system involvement may manifest as damage to any layer of the heart.
Symptomatic or asymptomatic pericardial involvement is present in up to 50% of patients.
Myocarditis, or mononuclear cell infiltration, is less common and may cause resting tachycardia and
electrocardiographic abnormalities. Valvular abnormalities primarily of the mitral and aortic valves
manifest as diffuse leaflet thickening that may be associated with dysfunction (stenosis and/or
regurgitation). Valvular (or so-called Libman-Sacks) endocarditis was more common prior to the
widespread use of steroids. This nonbacterial verrucous endocarditis takes the form of single or
multiple 1- to 3-mm warty deposits on any heart valve, distinctively on either surface of the leaflets.
By comparison, the vegetations in infective endocarditis are considerably larger, and those in
rheumatic heart disease are smaller and confined to the lines of closure of the valve leaflets.
An increasing number of patients have clinical evidence of coronary artery disease (angina,
myocardial infarction) owing to coronary atherosclerosis. This complication is noted particularly in
young patients with long-standing disease and especially in those who have been treated with
corticosteroids. The pathogenesis of accelerated coronary atherosclerosis is unclear but is probably
multifactorial. The traditional risk factors, including hypertension, obesity, and hyperlipidemia, are
more common in SLE patients than in control populations. In addition, immune complexes and
antiphospholipid antibodies may cause endothelial damage and promote atherosclerosis.
Spleen. Splenomegaly, capsular thickening, and follicular hyperplasia are common features. Central
penicilliary arteries may show concentric intimal and smooth muscle cell hyperplasia, producing so-
called onion-skin lesions.
Lungs. Pleuritis and pleural effusions are the most common pulmonary manifestations, affecting
almost 50% of patients. Alveolar injury with edema and hemorrhage is less common. In some cases,
there is chronic interstitial fibrosis and secondary pulmonary hypertension. None of these changes is
specific for SLE.
Other Organs and Tissues. LE, or hematoxylin, bodies in the bone marrow or other organs are
strongly indicative of SLE. Lymph nodes may be enlarged with hyperplastic follicles or even
demonstrate necrotizing lymphadenitis.
5. Clinical Features:
• butterfly rash over the face
• fever
• pain but no deformity in one or more peripheral joints (feet, ankles, knees, hips, --fingers, wrists,
elbows, shoulders)
• pleuritic chest pain
• photosensitivity
The following sections describe two syndromes in which the cutaneous involvement is the exclusive
or most prominent feature.
Chronic Discoid Lupus Erythematosus
Chronic discoid lupus erythematosus is a disease in which the skin manifestations may mimic SLE,
but systemic manifestations are rare. It is characterized by the presence of skin plaques showing
varying degrees of edema, erythema, scaliness, follicular plugging, and skin atrophy surrounded by
an elevated erythematous border. The face and scalp are usually affected, but widely disseminated
lesions occasionally occur. The disease is usually confined to the skin, but 5% to 10% of patients with
discoid lupus erythematosus develop multisystem manifestations after many years. Conversely, some
patients with SLE may have prominent discoid lesions in the skin. Approximately 35% of patients
show a positive ANA test, but antibodies to double-stranded DNA are rarely present.
Immunofluorescence studies of skin biopsy specimens show deposition of immunoglobulin and C3 at
the dermoepidermal junction similar to that in SLE.
Subacute Cutaneous Lupus Erythematosus
This condition also presents with predominant skin involvement and can be distinguished from
chronic discoid lupus erythematosus by several criteria. The skin rash in this disease tends to be
widespread, superficial, and nonscarring, although scarring lesions may occur in some patients. Most
patients have mild systemic symptoms consistent with SLE. Furthermore, there is a strong
association with antibodies to the SS-A antigen and with the HLA-DR3 genotype. Thus, the term
subacute cutaneous lupus erythematosus seems to define a group intermediate between SLE and
lupus erythematosus localized only to skin.
Drug-Induced Lupus Erythematosus
A lupus erythematosus–like syndrome may develop in patients receiving a variety of drugs, including
hydralazine, procainamide, isoniazid, and D-penicillamine, to name only a few. Many of these drugs
are associated with the development of ANAs, but most patients do not have symptoms of lupus
erythematosus. For example, 80% of patients receiving procainamide test positive for ANAs, but only
one third of these manifest clinical symptoms, such as arthralgias, fever, and serositis. Although
multiple organs are affected, renal and central nervous system involvement is distinctly uncommon.
There are serologic and genetic differences from classical SLE, as well. Antibodies specific for
double-stranded DNA are rare, but there is an extremely high frequency of antibodies specific for
histone. Persons with the HLA-DR4 allele are at a greater risk of developing lupus erythematosus
after administration of hydralazine. The disease remits after withdrawal of the offending drug.
RHEUMATOID ARTHRITIS
Rheumatoid arthritis is a chronic inflammatory disease that affects primarily the joints but may involve
extra-articular tissues such as the skin, blood vessels, lungs, and heart. Abundant evidence supports
the autoimmune nature of the disease. Because the principal manifestations of the disease are in the
joints .
6. SJÖGREN SYNDROME
Sjögren syndrome is a chronic disease characterized by dry eyes (keratoconjunctivitis sicca) and dry
mouth (xerostomia) resulting from immunologically mediated destruction of the lacrimal and salivary
glands. It occurs as an isolated disorder (primary form), also known as the sicca syndrome, or more
often in association with another autoimmune disease (secondary form). Among the associated
disorders, rheumatoid arthritis is the most common, but some patients have SLE, polymyositis,
scleroderma, vasculitis, mixed connective tissue disease, or thyroiditis.
Morphology. As mentioned earlier, lacrimal and salivary glands are the major targets of the disease,
although other exocrine glands, including those lining the respiratory and gastrointestinal tracts and
the vagina, may also be involved. The earliest histologic finding in both the major and the minor
salivary glands is periductal and perivascular lymphocytic infiltration. Eventually the lymphocytic
infiltrate becomes extensive ( Fig. 6-35 ), and in the larger salivary glands lymphoid follicles with
germinal centers may be seen. The ductal lining epithelial cells may show hyperplasia, thus
obstructing the ducts. Later there is atrophy of the acini, fibrosis, and hyalinization; still later in the
course atrophy and replacement of parenchyma with fat are seen. In some cases the lymphoid
infiltrate may be so intense as to give the appearance of a lymphoma. Indeed, these patients are at
high risk for development of B-cell lymphomas, and molecular assessments of clonality may be
necessary to distinguish intense reactive chronic inflammation from early involvement by lymphoma.
The lack of tears leads to drying of the corneal epithelium, which becomes inflamed, eroded, and
ulcerated; the oral mucosa may atrophy, with inflammatory fissuring and ulceration; and dryness and
crusting of the nose may lead to ulcerations and even perforation of the nasal septum.
Clinical Features:
-Sjögren syndrome occurs most commonly in women between the ages of 50 and 60
-Keratoconjunctivitis: produces blurring of vision, burning, and itching, and thick secretions
accumulate in the conjunctival sac
-Xerostomia: results in difficulty in swallowing solid foods, a decrease in the ability to taste, cracks
and fissures in the mouth, and dryness of the buccal mucosa
-Parotid gland enlargement
-dryness of the nasal mucosa
-epistaxis
-recurrent bronchitis, and pneumonitis
SYSTEMIC SCLEROSIS (SCLERODERMA)
Systemic sclerosis is a chronic disease characterized by: (1) chronic inflammation thought to be the
result of autoimmunity, (2) widespread damage to small blood vessels, and (3) progressive interstitial
and perivascular fibrosis in the skin and multiple organs.
Morphology. Virtually all organs can be involved in systemic sclerosis. Prominent changes occur in
the skin, alimentary tract, musculoskeletal system, and kidney, but lesions also are often present in
the blood vessels, heart, lungs, and peripheral nerves.
Skin. A great majority of patients have diffuse, sclerotic atrophy of the skin, which usually begins in
the fingers and distal regions of the upper extremities and extends proximally to involve the upper
arms, shoulders, neck, and face. Histologically, there are edema and perivascular infiltrates
containing CD4+ T cells, together with swelling and degeneration of collagen fibers, which become
eosinophilic. Capillaries and small arteries (150 to 500 μm in diameter) may show thickening of the
basal lamina, endothelial cell damage, and partial occlusion. With progression of the disease, there is
increasing fibrosis of the dermis, which becomes tightly bound to the subcutaneous structures. There
is marked increase of compact collagen in the dermis, usually with thinning of the epidermis, loss of
rete pegs, atrophy of the dermal appendages, and hyaline thickening of the walls of dermal arterioles
and capillaries. Focal and sometimes diffuse subcutaneous calcifications may develop, especially in
patients with the CREST syndrome. In advanced stages the fingers take on a tapered, clawlike
appearance with limitation of motion in the joints, and the face becomes a drawn mask. Loss of blood
supply may lead to cutaneous ulcerations and to atrophic changes in the terminal phalanges.
Sometimes the tips of the fingers undergo autoamputation.
7. Alimentary Tract. The alimentary tract is affected in approximately 90% of patients. Progressive
atrophy and collagenous fibrous replacement of the muscularis may develop at any level of the gut
but are most severe in the esophagus. The lower two thirds of the esophagus often develops a
rubber-hose inflexibility. The associated dysfunction of the lower esophageal sphincter gives rise to
gastroesophageal reflux and its complications, including Barrett metaplasia and strictures. The
mucosa is thinned and may be ulcerated, and there is excessive collagenization of the lamina propria
and submucosa. Loss of villi and microvilli in the small bowel is the anatomic basis for the
malabsorption syndrome sometimes encountered.
Musculoskeletal System. Inflammation of the synovium, associated with hypertrophy and
hyperplasia of the synovial soft tissues, is common in the early stages; fibrosis later ensues. These
changes are reminiscent of rheumatoid arthritis, but joint destruction is not common in systemic
sclerosis. In a small subset of patients (approximately 10%), inflammatory myositis indistinguishable
from polymyositis may develop.
Kidneys. Renal abnormalities occur in two thirds of patients with systemic sclerosis. The most
prominent are the vascular lesions. Interlobular arteries show intimal thickening as a result of
deposition of mucinous or finely collagenous material, which stains histochemically for glycoprotein
and acid mucopolysaccharides. There is also concentric proliferation of intimal cells. These changes
may resemble those seen in malignant hypertension, but in scleroderma the alterations are restricted
to vessels 150 to 500 μm in diameter and are not always associated with hypertension. Hypertension,
however, does occur in 30% of patients with scleroderma, and in 20% it takes an ominously rapid,
downhill course (malignant hypertension). In hypertensive patients, vascular alterations are more
pronounced and are often associated with fibrinoid necrosis involving the arterioles together with
thrombosis and infarction. Such patients often die of renal failure, which accounts for about 50% of
deaths in persons with this disease. There are no specific glomerular changes.
Lungs. The lungs are involved in more than 50% of individuals with systemic sclerosis. This
involvement may manifest as pulmonary hypertension and interstitial fibrosis. Pulmonary vasospasm,
secondary to pulmonary vascular endothelial dysfunction, is considered important in the pathogenesis
of pulmonary hypertension. Pulmonary fibrosis, when present, is indistinguishable from that seen in
idiopathic pulmonary fibrosis.
Heart. Pericarditis with effusion and myocardial fibrosis, along with thickening of intramyocardial
arterioles, occurs in one third of the patients. Clinical myocardial involvement, however, is less
common.
Clinical Features:
• Systemic sclerosis has a female-to-male ratio of 3 : 1
• peak incidence in the 50- to 60-year age group
• skin thickening
• Raynaud's phenomenon
Rejection of Tissue Transplants
Transplant rejection is discussed here because it involves several of the immunological reactions that
underlie immune-mediated inflammatory diseases. A major barrier to transplantation is the process of
rejection, in which the recipient's immune system recognizes the graft as being foreign and attacks it.
Mechanisms of Recognition and Rejection of Allografts
Rejection is a complex process in which both cell-mediated immunity and circulating antibodies play
a role]; moreover, the contributions of these two mechanisms are often reflected in the histologic
features of the rejected organs.
8. T Cell–Mediated Reactions
The critical role of T cells in transplant rejection has been documented both in humans and in
experimental animals. T cell–mediated graft rejection is called cellular rejection, and it involves
destruction of graft cells by CD8+ CTLs and delayed hypersensitivity reactions triggered by activated
CD4+ helper cells. The major antigenic differences between a donor and recipient that result in
rejection of transplants are differences in highly polymorphic HLA alleles. The recipient's T cells
recognize donor antigens from the graft (the allogeneic antigens, or alloantigens) by two pathways,
called direct and indirect.
Direct Pathways
T cells of the transplant recipient recognize allogeneic (donor) MHC molecules on the surface
of APCs in the graft. It is believed that dendritic cells carried in the donor organs are the most
important APCs for initiating the antigraft response, because they not only express high levels of
class I and II MHC molecules but also are endowed with costimulatory molecules (e.g., B7-1 and
B7-2). The T cells of the host encounter the donor dendritic cells either within the grafted organ or
after the dendritic cells migrate to the draining lymph nodes. CD8+ T cells recognize class I MHC
mdecules and differentiate into active CTLs, which can kill the graft cells by mechanisms already
discussed. CD4+ helper T cells recognize allogeneic class II molecules and proliferate and
differentiate into TH1 (and possibly TH17) effector cells. Cytokines secreted by the activated CD4+ T
cells trigger a delayed hypersensitivity reaction in the graft, resulting in increased vascular
permeability and local accumulation of mononuclear cells (lymphocytes and macrophages), and graft
injury caused by the activated macrophages. The direct recognition of allogeneic MHC molecules
seems paradoxical to the rules of self-MHC restriction: If T cells normally are restricted to recognizing
foreign peptides displayed by self-MHC molecules, why should these T cells recognize foreign MHC?
The probable explanation is that allogeneic MHC molecules, with their bound peptides, resemble, or
mimic, the self-MHC–foreign peptide complexes that are recognized by self-MHC–restricted T cells.
Thus, recognition of allogeneic MHC molecules is a cross-reaction of T cells selected to recognize
self-MHC plus foreign peptides.
Indirect pathways
Recipient T lymphocytes recognize MHC antigens of the graft donor after they are presented by the
recipient's own APCs. This process involves the uptake and processing of MHC and other foreign
molecules from the grafted organ by host APCs. The peptides derived from the donor tissue are
presented by the host's own MHC molecules, like any other foreign peptide. Thus, the indirect
pathway is similar to the physiologic processing and presentation of other foreign (e.g., microbial)
antigens. The indirect pathway generates CD4+ T cells that enter the graft and recognize graft
antigens being displayed by host APCs that have also entered the graft, and the result is a delayed
hypersensitivity type of reaction. However, CD8+ CTLs that may be generated by the indirect
pathway cannot directly recognize or kill graft cells, because these CTLs recognize graft antigens
presented by the host's APCs. Therefore, when T cells react to a graft by the indirect pathway, the
principal mechanism of cellular rejection may be T-cell cytokine production and delayed
hypersensitivity. It is postulated that the direct pathway is the major pathway in acute cellular
rejection, whereas the indirect pathway is more important in chronic rejection. However, this
separation is by no means absolute.
Antibody-Mediated Reactions
Although T cells are pivotal in the rejection of organ transplants, antibodies produced against
alloantigens in the graft are also important mediators of rejection. This process is called humoral
rejection, and it can take two forms. Hyperacute rejection occurs when preformed antidonor
antibodies are present in the circulation of the recipient. Such antibodies may be present in a
recipient who has previously rejected a kidney transplant. Multiparous women who develop anti-HLA
antibodies against paternal antigens shed from the fetus may have preformed antibodies to grafts
taken from their husbands or children, or even from unrelated individuals who share HLA alleles with
the husbands. Prior blood transfusions can also lead to presensitization, because platelets and white
blood cells are rich in HLA antigens and donors and recipients are usually not HLA-identical. With the
9. current practice of cross-matching, that is, testing recipient's serum for antibodies against donor's
cells, hyperacute rejection is no longer a significant clinical problem.
Rejection of Kidney Grafts
Morphology. On the basis of the morphology and the underlying mechanism, rejection reactions
are classified as hyperacute, acute, and chronic. The morphologic changes in these patterns are
described below as they relate to renal transplants. Similar changes may occur in any other
vascularized organ transplant and are discussed in relevant chapters.
Hyperacute Rejection. This form of rejection occurs within minutes or hours after transplantation. A
hyperacutely rejecting kidney rapidly becomes cyanotic, mottled, and flaccid, and may excrete a mere
few drops of bloody urine. Immunoglobulin and complement are deposited in the vessel wall, causing
endothelial injury and fibrin-platelet thrombi. Neutrophils rapidly accumulate within arterioles,
glomeruli, and peritubular capillaries. As these changes become diffuse and intense, the glomeruli
undergo thrombotic occlusion of the capillaries, and fibrinoid necrosis occurs in arterial walls. The
kidney cortex then undergoes outright necrosis (infarction), and such nonfunctioning kidneys have to
be removed.
Acute Rejection. This may occur within days of transplantation in the untreated recipient or may
appear suddenly months or even years later, after immunosuppression has been used and
terminated. In any one patient, cellular or humoral immune mechanisms may predominate.
Histologically, humoral rejection is associated with vasculitis, whereas cellular rejection is marked by
an interstitial mononuclear cell infiltrate.
Acute cellular rejection is most commonly seen within the initial months after transplantation and is
heralded by clinical and biochemical signs of renal failure. Histologically, there may be extensive
interstitial mononuclear cell infiltration and edema as well as mild interstitial hemorrhage. As might be
expected, immunohistochemical staining reveals both CD4+ and CD8+ T lymphocytes, which express
markers of activated T cells, such as the α chain of the IL-2 receptor. Glomerular and peritubular
capillaries contain large numbers of mononuclear cells that may also invade the tubules, causing
focal tubular necrosis. In addition to causing tubular damage, CD8+ T cells may injure vascular
endothelial cells, causing a so-called endothelitis. The affected vessels have swollen endothelial
cells, and at places the lymphocytes can be seen between the endothelium and the vessel wall. The
recognition of cellular rejection is important because, in the absence of an accompanying humoral
rejection, patients respond well to immunosuppressive therapy. Cyclosporine, a widely used
immunosuppressive drug, is also nephrotoxic, and hence the histologic changes resulting from
cyclosporine may be superimposed.
Acute humoral rejection (rejection vasculitis) is mediated by antidonor antibodies, and hence it is
manifested mainly by damage to the blood vessels. This may take the form of necrotizing vasculitis
with endothelial cell necrosis, neutrophilic infiltration, deposition of immunoglobulins, complement,
and fibrin, and thrombosis. Such lesions are associated with extensive necrosis of the renal
parenchyma. In many cases, the vasculitis is less acute and is characterized by marked thickening of
the intima with proliferating fibroblasts, myocytes, and foamy macrophages. The resultant narrowing
of the arterioles may cause infarction or renal cortical atrophy. The proliferative vascular lesions
mimic arteriosclerotic thickening and are believed to be caused by cytokines that cause proliferation
of vascular smooth muscle cells. Deposition of the complement breakdown product C4d in allografts
is a strong indicator of humoral rejection, because C4d is produced during activation of the
complement system by the antibody-dependent classical pathway. The importance of making this
diagnosis is that it provides a rationale for treating affected patients with B cell–depleting agents.
Chronic Rejection. In recent years acute rejection has been significantly controlled by
immunosuppressive therapy, and chronic rejection has emerged as an important cause of graft
failure. Patients with chronic rejection present clinically with a progressive renal failure manifested by
a rise in serum creatinine over a period of 4 to 6 months. Chronic rejection is dominated by vascular
changes, interstitial fibrosis, and tubular atrophy with loss of renal parenchyma. The vascular
changes consist of dense, obliterative intimal fibrosis, principally in the cortical arteries. These
vascular lesions result in renal ischemia, manifested by glomerular loss, interstitial fibrosis and tubular
atrophy, and shrinkage of the renal parenchyma. The glomeruli may show scarring, with duplication of
10. basement membranes; this appearance is sometimes called chronic transplant glomerulopathy.
Chronically rejecting kidneys usually have interstitial mononuclear cell infiltrates of plasma cells and
numerous eosinophils.
Immunodeficiency Syndromes
-Primary Immunodeficiency Disorders
-Secondary Immunodeficiency State
PRIMARY IMMUNODEFICIENCIES
- are genetically determined and affect the humoral and/or cellular arms of adaptive immunity
(mediated by B and T lymphocytes, respectively) or the defense mechanisms of innate immunity (NK
cells, phagocytes, or complement). Defects in adaptive immunity are often subclassified on the basis
of the primary component involved (i.e., B cells or T cells or both).
-Most primary immunodeficiencies manifest themselves in infancy, between 6 months and 2 years of
life, and they are detected because the affected infants are susceptible to recurrent infections
Examples of Infections in Immunodeficiencies
Pathogen Granulocyte Complement
Type T-Cell Defect B-Cell Defect Defect Defect
Bacteria Bacterial sepsis Streptococci, Staphylococci, Neisserial
staphylococci, Pseudomonas infections, other
Haemophilus pyogenic
Viruses Cytomegalovirus, Enteroviral infections
Epstein-Barr virus, encephalitis
severe varicella,
chronic infections with
respiratory and
intestinal viruses
Fungi and Candida, Severe intestinal Candida,
parasites Pneumocystis jiroveci giardiasis Nocardia,
Aspergillus
Special Aggressive disease Recurrent
features with opportunistic sinopulmonary
pathogens, failure to infections, sepsis,
clear infections chronic meningitis
X-Linked Agammaglobulinemia (Bruton's Agammaglobulinemia)
• one of the more common forms of primary immunodeficiency
• It is characterized by the failure of B-cell precursors to develop into mature B cells.
• caused by mutations in a cytoplasmic tyrosine kinase, called Bruton tyrosine kinase (Btk)
*Btk is a protein tyrosine kinase that is associated with the Ig receptor complex of pre-B
and mature B cells and is needed to transduce signals from the receptor.
• seen almost entirely in males, but sporadic cases have been described in females
• The disease usually does not become apparent until about 6 months of age, as maternal
immunoglobulins are depleted
11. • Prophylactic intravenous Ig therapy allows most individuals to reach adulthood.
Bacterial Infections of the Respiratory Tract
• Acute and Chronic Pharyngitis
• Sinusitis
• Otitis media
• Bronchitis
• Pneumonia
Causative Organism
• Haemophilus influenzae
• Streptococcus pneumoniae
• Staphylococcus aureus
Viral Infections:
• Echovirus
• Poliovirus
• Coxsackievirus
• Giardia lamblia
- an intestinal protozoan that is normally resisted by secreted IgA, causes persistent infections
in persons with this disorder.
The classic form of this disease has the following characteristics:
B cells are absent or markedly decreased in the circulation, and the serum levels of all classes of
immunoglobulins are depressed. Pre-B cells, which express the B-lineage marker CD19 but not
membrane Ig, are found in normal numbers in the bone marrow.
• Germinal centers of lymph nodes, Peyer's patches, the appendix, and tonsils are
underdeveloped.
• Plasma cells are absent throughout the body.
• T cell–mediated reactions are normal.
Common Variable Immunodeficiency
• relatively common but poorly defined entity represents a heterogeneous group of disorders
• Hypogammaglobulinemia - generally affecting all the antibody classes but sometimes only
IgG.
• It is based on exclusion of other well-defined causes of decreased antibody production.
• most individuals have normal or near-normal numbers of B cells in the blood and lymphoid
tissues.
• affects both sexes equally – onset of symptoms is later in childhood or adolescence
12. Clinical Manifestations of Common Variable Immunodeficiency
• recurrent sinopulmonary pyogenic infections
• recurrent herpesvirus infections
• meningoencephalitis
• persistent diarrhea
Isolated IgA Deficiency
• is a common immunodeficiency
• European descent, it is far less common in blacks and Asians
• Affected individuals have extremely low levels of both serum and secretory IgA
• It may be familial, or acquired in association with toxoplasmosis, measles, or some other viral
infection
• Most individuals with this disease are asymptomatic.
• IgA is the major Ig in external secretions, mucosal defenses are weakened, and infections
occur in the respiratory, gastrointestinal, and urogenital tracts
• Some individuals with IgA deficiency are also deficient in the IgG2 and IgG4 subclasses of
IgG.
• IgA-deficient patients have a high frequency of respiratory tract allergy and a variety of
autoimmune diseases, particularly SLE and rheumatoid arthritis.
• When transfused with blood containing normal IgA, some of these patients develop severe,
even fatal, anaphylactic reactions, because the IgA behaves like a foreign antigen (since the
patients do not produce it and are not tolerant to it).
• Impaired differentiation of naive B lymphocytes to IgA-producing cells.
Hyper-IgM Syndrome
• affected patients make IgM antibodies but are deficient in their ability to produce IgG, IgA, and
IgE antibodies.
• It is inherited in an autosomal recessive pattern
• The number of B and T cells is normal.
• Many of the IgM antibodies react with elements of blood, giving rise to autoimmune hemolytic
anemia, thrombocytopenia, and neutropenia. In older patients there may be uncontrolled
proliferation of IgM-producing plasma cells with infiltrations of the gastrointestinal tract.
Although the proliferating B cells are polyclonal, extensive infiltration may lead to death.
• individuals with the hyper-IgM syndrome present with recurrent pyogenic infections, because
the level of opsonizing IgG antibodies is low. In addition, those with CD40L mutations are also
susceptible to pneumonia caused by the intracellular organism Pneumocystis jiroveci, because
of the defect in cell-mediated immunity.
DiGeorge Syndrome (Thymic Hypoplasia)
13. • is a T-cell deficiency that results from failure of development of the third and fourth pharyngeal
pouches
• individuals with this syndrome have a variable loss of T cell–mediated immunity, tetany and
congenital defects of the heart and great vessels.
• Not a familial disorder
Severe Combined Immunodeficiency
• represents a constellation of genetically distinct syndromes, all having in common defects in
both humoral and cell-mediated immune responses.
• Affected infants present with prominent thrush, extensive diaper rash, and failure to thrive.
• Some patients develop a morbilliform rash shortly after birth because maternal T cells are
transferred across the placenta and attack the fetus, causing GVH disease.
• 50%- 60% of cases is a X-linked
• extremely susceptible to recurrent, severe infections by a wide range of pathogens, including
Candida albicans, P. jiroveci, Pseudomonas, cytomegalovirus, varicella, and a whole host of
bacteria
• The remaining cases of SCID are inherited as autosomal recessive. The most common cause
of autosomal recessive SCID is a deficiency of the enzyme adenosine deaminase (ADA).
Although the mechanisms by which ADA deficiency causes SCID are not entirely clear, it has
been proposed that deficiency of ADA leads to accumulation of deoxyadenosine and its
derivatives (e.g., deoxy-ATP), which are toxic to rapidly dividing immature lymphocytes,
especially those of the T-cell lineage
• Bone marrow transplantation – is the mainstay treatment
• Gene therapy – x-linked SCID, is the first human disease that has been successful
Several other less common causes of autosomal recessive SCID have been
discovered
• Mutations in recombinase-activating genes prevent the somatic gene rearrangements
essential for the assembly of T-cell receptor and Ig genes. This blocks the development of T
and B cells.
• An intracellular kinase called Jak3 is essential for signal transduction through the common
cytokine receptor γ chain (which is mutated in X-linked SCID, as discussed above). Mutations
of Jak3 therefore have the same effects as mutations in the γc chain.
• Several mutations have been described in signaling molecules, including kinases associated
with the T-cell antigen receptor and components of calcium channels that are required for entry
of calcium and activation of many signaling pathways.
• Mutations that impair the expression of class II MHC molecules prevent the development of
CD4+ T cells. CD4+ T cells are involved in cellular immunity and provide help to B cells, and
hence class II MHC deficiency results in combined immunodeficiency. This disease, called the
bare lymphocyte syndrome, is usually caused by mutations in transcription factors that are
required for class II MHC gene expression.
14. Immunodeficiency with Thrombocytopenia and Eczema (Wiskott-Aldrich
Syndrome)
• is an X-linked recessive disease characterized by thrombocytopenia, eczema, and a marked
vulnerability to recurrent infection, ending in early death
• is caused by mutations in the gene encoding Wiskott-Aldrich syndrome protein (WASP) This
protein belongs to a family of proteins that are believed to link membrane receptors, such as
antigen receptors, to cytoskeletal elements. The WASP protein may be involved in
cytoskeleton-dependent responses, including cell migration and signal transduction, but the
essential functions of this protein in lymphocytes and platelets are unclear
• Bone marrow transplantation
Genetic Deficiencies of the Complement System
• The complement system plays critical roles in host defense and inflammation
• A deficiency of C2 is the most common of all. With a deficiency of C2 or the other early
components of the classical pathway there is little or no increase in susceptibility to infections,
but the dominant manifestation is an increased incidence of an SLE-like autoimmune disease
• There is also increased incidence of immune complex–mediated glomerulonephritis; in the
absence of complement, immune complex–mediated inflammation is presumably caused by
Fc receptor–dependent leukocyte activation.
• A deficiency of C1 inhibitor gives rise to hereditary angioedema.
• This autosomal dominant disorder is more common than complement deficiency states.
SECONDARY IMMUNODEFICIENCIES
• may be encountered in individuals with cancer, diabetes and other metabolic diseases,
malnutrition, chronic infection, and renal disease
• They also occur in persons receiving chemotherapy or radiation therapy for cancer, or
immunosuppressive drugs to prevent graft rejection or to treat autoimmune diseases.
• can be caused by defective lymphocyte maturation (when the bone marrow is damaged by
radiation or chemotherapy or involved by tumors, such as leukemias and metastatic cancers),
loss of immunoglobulins (as in proteinuric renal diseases), inadequate Ig synthesis (as in
malnutrition), or lymphocyte depletion (from drugs or severe infections). As a group, the
secondary immune deficiencies are more common than the disorders of primary genetic origin.
ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS)
- is a disease caused by the retrovirus human immunodeficiency virus (HIV) and characterized by
profound immunosuppression that leads to opportunistic infections, secondary neoplasms, and
neurologic manifestations
Epidemiology
• Homosexual or bisexual men constitute the largest group, accounting for over 50% of the
reported cases.
• Intravenous drug abusers with no previous history of homosexuality are the next largest group,
representing about 20% of infected individuals.
15. • Hemophiliacs, especially those who received large amounts of factor VIII or factor IX
concentrates before 1985, make up about 0.5% of all cases.
• Recipients of blood and blood components who are not hemophiliacs but who received
transfusions of HIV-infected whole blood or components account for about 1% of patients.
• Heterosexual contacts of members of other high-risk groups constitute about 10% of the
patient population.
• In approximately 5% of cases the risk factors cannot be determined.
Routes of Transmission
• Sexual Contact
• Parental Inoculation
• Passage of the virus from infected mothers to their newborns
Sexual Contact
Sexual Transmission
is clearly the predominant mode of infection worldwide, accounting for over 75% of all cases of
HIV transmission
Viral Transmission
• (1) direct inoculation into the blood vessels breached by trauma
• (2) infection of dendritic cells or CD4+ cells within the mucosa
Heterosexual Transmission
-is globally the most common mode by which HIV is spread
Sexually Transmitted Disease
• Syphillis
• Chancroid
• Herpes
• Gonorrhea
• Chlamydia
Parenteral transmission
three groups of individuals:
• intravenous drug abusers
• hemophiliacs who received factor VIII and factor IX concentrates
• random recipients of blood transfusion
Mother-to-infant transmission
- is the major cause of pediatric AIDS.
16. three routes:
(1) in utero by transplacental spread
(2) during delivery through an infected birth canal
(3) after birth by ingestion of breast milk.
Etiology: The Properties of HIV
AIDS is caused by HIV, a nontransforming human retrovirus belonging to the lentivirus family.
Included in this group are feline immunodeficiency virus, simian immunodeficiency virus, visna virus
of sheep, bovine immunodeficiency virus, and the equine infectious anemia virus.
Pathogenesis of HIV Infection and AIDS
• Profound immune deficiency, primarily affecting cell-mediated immunity, is the hallmark of
AIDS. This results chiefly from infection of and a severe loss of CD4+ T cells as well as
impairment in the function of surviving helper T cells
two major targets of HIV infection:
• the immune system
• the central nervous system
Pathogenesis of Central Nervous System Involvement
• nervous system is a major target of HIV infection
• Macrophages and microglia, cells in the central nervous system that belong to the
macrophage lineage, are the predominant cell types in the brain that are infected with HIV
Natural History of HIV Infection
HIV disease begins with acute infection, which is only partly controlled by the adaptive immune
response, and advances to chronic progressive infection of peripheral lymphoid tissues phases:
(1) an acute retroviral syndrome;
(2) a middle, chronic phase, in which most individuals are asymptomatic; and
(3) clinical AIDS
Primary Infection, Virus Dissemination, and the Acute Retroviral Syndrome
Acute (early) infection
is characterized by infection of memory CD4+ T cells in mu-cosal lymphoid tissues, and death
of many infected cells. Because the mucosal tissues are the largest reservoir of T cells in the body,
and a major site of residence of memory T cells, this local loss results in considerable depletion of
lymphocytes. Few infected cells are detectable in the blood and other tissues.
Mucosal infection
is followed by dissemination of the virus and the development of host immune responses.
17. Acute retroviral syndrome
• is the clinical presentation of the initial spread of the virus and the host response.
.
*chronic phase of the disease, lymph nodes and the spleen are sites of continuous HIV replication
and cell destruction
Clinical latency period
• few or no clinical manifestations of the HIV infection are present
AIDS
• breakdown of host defense, a dramatic increase in plasma virus, and severe, life-threatening
clinical disease
• with long-lasting fever (>1 month), fatigue, weight loss, and diarrhea. After a variable period,
serious opportunistic infections, secondary neoplasms, or clinical neurologic disease (grouped
under the rubric AIDS indicator diseases, discussed below) emerge
rapid progressors the middle, chronic phase is telescoped to 2 to 3 years after primary infection.
long-term nonprogressors defined as untreated HIV-1–infected individuals who remain
asymptomatic for 10 years or more
Clinical Features of AIDS
• Fever
• weight loss
• diarrhea
• generalized lymphadenopathy
• multiple opportunistic infections
• neurologic disease
• secondary neoplasms
Amyloidosis
• is a pathologic proteinaceous substance, deposited in the extracellular space in various tissues
and organs of the body in a wide variety of clinical settings
• should not be considered a single disease; rather it is a group of diseases having in common
the deposition of similar-appearing proteins
• a variety of histochemical techniques are used.
*Congo red stain, which under ordinary light imparts a pink or red color to tissue deposits, but far
more striking and specific is the green birefringence of the stained amyloid when observed by
polarizing microscopy
18. Properties of Amyloid Proteins
• Physical Nature of Amyloid
• Chemical Nature of Amyloid
Pathogenesis of Amyloidosis
• results from abnormal folding of proteins, which are deposited as fibrils in extracellular tissues
and disrupt normal function
two general categories:
(1) normal proteins that have an inherent tendency to fold improperly, associate and form fibrils,
and do so when they are produced in increased amounts
(2) mutant proteins that are prone to misfolding and subsequent aggregation.
Classification of Amyloidosis:
• Primary Amyloidosis: Immunocyte Dyscrasias with Amyloidosis
• Reactive Systemic Amyloidosis
• Hemodialysis-Associated Amyloidosis
• Heredofamilial Amyloidosis
• Localized Amyloidosis
• Endocrine Amyloid
• Amyloid of Aging