IMMUNOLOGY & SEROLOGY – Autoimmune Diseases

Autoimmunity
• Expression of the immune response that occurs when the body’s self-tolerance system fails
• The body immune cells are no longer able to recognize “self” and resulting to an immune response against its own
antigens
• Mechanisms:
1. Release of sequestered antigens
o Antigens that ordinarily do not encounter antibody forming cells
o Accidentally released in the circulation after damage and elicit humoral and cellular responses upon
exposure to the immune system
2. Self antigens are slightly altered and the body makes antibodies to these self antigens
3. Cross-reacting (heterophile) or closely related antibody
4. The spontaneous emergence of clones of cells (forbidden clones) capable of making an immune response to
one’s own tissues
5. Deficiency of T suppressor cells (results in autoimmunity)

Autoimmune disease
• Occurs when an individual produces antibodies or a T cell response to his/her own antigens
• Occurrence of an immune response resulting in the production of either antibody and/or sensitized lymphoid cells
capable of reacting with normal body constituents
• The autoimmune response involves either class I but most especially class II MHC proteins
• All autoimmune diseases involve antigen-antibody complexes (immune complexes)
• Autoimmune Mechanisms:
a. Antibody-cell surface component interaction
b. Formation of autoantigen-autoantibody complexes
c. Sensitization of T cells
d. Genetic factors play a role in the development of autoimmune diseases; the presence of certain HLA types has
been correlated with specific diseases
HLA Type Associated Diseases
HLA-B8 Graves’ disease and type 1 diabetes
HLA-DR2 SLE, multiple sclerosis, Hashimoto disease, and myasthenia gravis
HLA-DR3 Sjogren’s syndrome, myasthenia gravis, SLE, Graves’ disease, and type 1 diabetes
HLA-DR4 Rheumatoid arthritis, type 1 diabetes, and pemphigus vulgaris

• Autoimmune Theories:
1. Forbidden-clone theory
o Burnet postulated that when an error in self-recognition occurs during fetal life and lymphocytes against an
autoantigen are not destroyed, then autoantibodies are produced
2. Clonal anergy
o Clones developed during fetal life are not stimulated by low doses of antigens
o The ability to produce antibodies against higher doses of antigens is still present
3. Sequestered-antigen theory
o Some antigens are hidden from the immune system during fetal development
o When the tissue is damaged, the “hidden cells” are exposed to the immune system and antibodies are
formed against these cells
4. Immunologic deficiency theory
o Suppressor T cells control antibody production by B cells
o If suppressor T cells exhibit decreased activity, then antibodies against autoantigens are produced
5. Molecular mimicry
o An individual can make antibodies or reactive T cells to an infectious agent that cross react with self antigens
6. Polyclonal B cell activation
o A number of bacteria and viruses are known to nonspecifically stimulate B cells
o If these B cells have activity against self-antigens, an autoimmune disease can result

• Signs of autoimmune disease:
1. Increase in the amount of gamma globulin
2. Occurrence of different autoantibodies which are detected in the serum
3. Decreased concentration of complement in serum
4. Absence of CD8+ lymphocytes
5. Immunoglobulin and complement deposits in the arterial walls and basement membrane
6. Lesions detected in biopsy resulting from deposition of immune complexes
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• Diagnostic Test for Non-Organ-Specific Autoimmune Diseases:
1. Antinuclear antibodies (ANAs)
o Associated with systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), and
rheumatoid arthritis
o Techniques used to detect ANA: agglutination, indirect immunofluorescence, and enzyme immunoassay
o Interpretation of indirect immunofluorescence assay (IFA) results:
1.) Diffuse or homogenous: evenly stains the nuclei and is associated with anti-DNA antibody and histones
o Solid, diffuse
o Characterizes:
• Anti-deoxyribonucleoprotein (DNP) antibodies (i.e. antibodies to nDNA, dsDNA, ssDNA, DNP or
histones)
o Associated with:
• Typically seen in rheumatoid arthritis
• High titers of homogenous ANA are suggestive of SLE
• Low titers may be found in SLE, RA, Sjogren’s syndrome and Mixed Connective Tissue Disease
(MCTD)

2.) Peripheral: stains the edge of the nuclei and is associated with anti-DNA antibody and anti-lamins
antibody
o Ring, membranous, shaggy or thread
o Pattern results from antibodies to DNA
o Due to:
• Anti-dsDNA
o Associated with:
• Active stage of SLE
• Sjogren’s syndrome

3.) Speckled: numerous evenly distributed stained speckles within the nuclei associated with antibodies to
extractable nuclear antigens → nuclear ribonucleoprotein (RNP) and anti-Smith (Sm)
o Pattern occurs in the presence of antibody to any extractable nuclear antigen devoid of DNA or
histone
o Due to:
• Anti-extractable nuclear Ag (ENA)
• Anti-Smith (Sm)
• Anti-ribonucleoprotein (RNP) → has been found in patients with wide variety of rheumatic
diseases including SLE, RA, Sjogren’s syndrome, progressive systemic sclerosis, MCTD and
dermatomyositis

4.) Nucleolar: stains two or three large fluorescent areas within the nucleus and is associated with anti-RNP
antibody
o Reflects:
• Antibody to nucleolar RNA
o Present in about 50% patients with scleroderma (progressive systemic sclerosis), Sjogren’s
syndrome and in SLE

5.) Centromere: stains as a discrete speckled pattern due to anti-centromere antibody
o Antibody reacts with the centromeric chromatin of metaphase and interphase cells
o Due to:
• Anti-centromere antibody (ACA)
o Appears to be highly selective for CREST variant of progressive systemic sclerosis

2. Rheumatoid factor
o Rheumatoid factor (RF) is an anti-antibody, typically IgM, that binds to the Fc portion of abnormal IgG
o Also noted in chronic hepatitis, SLE and syphilis
o RF is usually detected by latex agglutination: Patient serum is mixed with IgG-coated latex particles →
agglutination indicates the presence of RF

3. Cryoglobulins
o Proteins that reversibly precipitate at 4°C
o Associated with autoimmune diseases such as vasculitis, glomerulonephritis, SLE, RA, and Sjogren’s
syndrome

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 Note: Autoantibodies and Disease Association:
Autoantibody Disease Association
CREST (calcinosis, Raynaud syndrome, esophageal hypomotility, sclerodactyly,
Centromere
and telangiectasia) syndrome
Found in SLE and low titers found in rheumatoid arthritis and Sjogren’s
dsDNA
syndrome
Histone Drug-induced SLE
Nuclear RNP SLE and mixed connective tissue disease
Scl-70 Scleroderma (systemic sclerosis)
Sjogren’s syndrome A (SSA [Ro]) Sjogren’s syndrome and SLE
Sjogren’s syndrome B (SSB [LA]) Sjogren’s syndrome and SLE
Sm Diagnostic for SLE (high specificity) if present but low sensitivity

Autoimmune Diseases
• Spectrum Of Autoimmune Diseases:
Specificity Disease Target Tissue
Organ specific Hashimoto’s thyroiditis Thyroid
Graves’ disease Thyroid
Pernicious anemia Gastric parietal cells
Addison’s disease Adrenal glands
Insulin-dependent diabetes mellitus Pancreas
Myasthenia gravis Nerve-muscle synapses
Multiple sclerosis Myelin sheath of nerves
Autoimmune hemolytic anemia Red blood cells
Idiopathic thrombocytopenic purpura Platelets
Goodpasture’s syndrome Kidney, lung
Rheumatoid arthritis Joints, lungs, skin
Scleroderma Skin, gut, lungs, kidney
Systemic Systemic lupus erythematosus Skin, joints, kidney, brain, heart, lungs

1. Non-Organ Specific
a. Systemic Lupus Erythematosus (SLE)
• Chronic inflammatory autoimmune disease characterized by the presence of antinuclear antibodies
• Symptoms may include swelling of the joints, erythematous rash and deposition of immune complexes in
the kidneys
• Severity of disease varies – symptoms include fever, weight loss, malaise, weakness, arthritis, skin lesions,
photosensitivity, butterfly rash (rash across the cheeks and bridge of the nose), renal disease, pericarditis,
seizures, ocular changes, pancreatitis, and small-vessel vasculitis
• Laboratory diagnosis of SLE:
1) Demonstration of LE cell
o Neutrophil has engulfed the antibody-coated nucleus of another neutrophil
2) Detection of antinuclear antibodies
o Homogenous or peripheral à request _________________________
• If positive: anti-dsDNA (SLE)
• If negative: consider anti-DNP (LE factor)

b. Rheumatoid arthritis (RA)
• Autoimmune disease that affects the synovial membrane of multiple joints
• Chronic, noninfectious, systemic inflammatory disease that primarily affects the joints
• Characterized by the presence of an autoantibody called rheumatoid factor (RF)
• The disease is due to production of IgG or IgM antibodies against IgG in the synovium
o Immune complexes form, which activate complement; the inflammatory response proceeds and
damages the synovium
o Immune complexes attract neutrophils and macrophages to the joint that degranulated and contribute
to tissue destruction
• Symptoms are highly variable and include fatigue, weight loss, weakness, mild fever, anorexia, morning
stiffness, joint pain (that improves during the day), vasculitis, and rheumatoid nodules
• Laboratory findings include elevated erythrocytic sedimentation rate (ESR), elevated CRP, positive RF,
cryoglobulins, and sometimes ANAs
o Synovial fluid is cloudy, with a WBC count between 5,000 and 20,000/µL, elevated protein, poor mucin
clot development, decreased complement and positive RF

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 •Laboratory diagnosis of RA: Based on the detection of RF
1) Sheep cell agglutination test: Rose-Waaler Test
2) Latex fixation test: Singer and Plotz
3) Sensitized alligator erythrocyte test: Cohen et.al
4) Bentonite flocculation test: Bloch and Bunim
• Note: Anti-cyclic citrullinated peptide antibody (anti-CCP)

c. Sjogren’s syndrome
• An inflammation of salivary and lacrimal glands causing dryness of mouth and eyes
• Laboratory findings include polyclonal hypergammaglobulinemia; autoantibodies against the salivary glands;
and positive RF, ANA (speckled or diffuse pattern), anti-SSA, and anti-SSB

d. Autoimmune hemolytic anemia
• Increased rate of RBC destruction
• Results in normocytic, normochromic anemia
• Autoantibody is directed against RBC antigens
• Laboratory findings include positive direct antiglobulin test and sometimes cold agglutinins

2. Organ-Specific
Autoimmune Disease Autoantibodies Associated
Addison’s disease Antibody to adrenal cells
o Target organ or tissue: adrenal glands
o Non-tuberculous chronic adrenocortical insufficiency
o 21-hydroxylase and 17α-hydroxylase are two autoantigens that have
been identified as reactive with adrenocortical autoantibodies
o Plasma cortisol levels are also low and adrenocorticotropic hormone
levels are elevated

Autoimmune hemolytic anemia Antibody to RBCs

o Target organ or tissue: Red blood cells
o These include warm antibody hemolytic anemia (most common), cold
antibody hemolytic anemia and paroxysmal cold hemoglobinuria

Autoimmune idiopathic thrombocytopenic purpura Antibody to platelets

o This may be either acute or chronic, and a result of antibody-
mediated platelet destruction

Chronic active hepatitis Anti-smooth muscle antibodies

o Liver disease

Inflammatory bowel disease Perinuclear anti-neutrophil

o Crohn’s disease: 10-30% p-ANCA cytoplasmic antibodies (p-ANCA)
o Ulcerative colitis: 60-80% p-ANCA Antibody to Saccharomyces cerevisiae
(Crohn’s disease)

Goodpasture’s syndrome Antibodies to glomerular and alveolar

o Rare progressive disease of the lungs and kidney basement membranes
o Linear deposits of immunoglobulin (usually lgG) and complement are
present on alveolar and glomerular basement membrane

Graves’ disease Anti-TSH receptor antibodies

o The disease is characterized by hyperplasia and diffuse goiter caused
by an autoantibody reacting to thyroid receptor on cells that
overstimulates the thyroid gland → the autoantibody mimics the
activity of thyroid-stimulating hormone (TSH)
o Thyrotoxicosis results from overstimulation; both free and total T3
and T4 are elevated, and TSH is decreased
o Common findings: exophthalmos (bulging eyes) and infiltrative
dermopathy

Hashimoto’s thyroiditis Anti-thyroid peroxidase antibodies

o Destruction of the thyroid gland (anti-microsomal antibodies) and
o Humoral and cellular immunity are activated and destruction of second colloid antigen (CA-2)
normal thyroid tissue leads to hypothyroidism, loss of thyroid Anti-thyroglobulin antibodies
function, and low levels of thyroid hormones in the blood

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 Multiple sclerosis Anti-myelin sheath antibodies
o Relapsing neuromuscular disease with periods of exacerbation and
remission
o Considered a chronic progressive inflammatory disease with
demyelinization of the nerves

Myasthenia gravis Anti-acetylcholine esterase antibodies

o Tissue (nerve and muscle) with systemic effects
o Neuromuscular transmission disorder
o Antibodies are inhibitory and block acetylcholine binding
o Some evidence of prior infection with poliovirus

Pernicious anemia Antibody to parietal cells

o Target organ: stomach Antibody to intrinsic factor
o Destruction of the parietal cells of the stomach mucosa leading to
intrinsic factor deficiency

Primary biliary cirrhosis Anti-mitochondrial antibodies

o T cell-mediated immune injury to intrahepatic interlobular bile ducts
dominates tissue lesions

Primary sclerosing cholangitis Perinuclear anti-neutrophil

o Fibrous cholangitis of large and/or small bile ducts cytoplasmic antibodies
o Wide spectrum of chronic inflammatory lesions is seen on liver biopsy

Rheumatoid arthritis Antibodies to the Fc portion of IgG

o Chronic systemic inflammatory disorder in which joint cartilage,
ligaments and tendons are destroyed

Scleroderma Anti-centromere antibody

o Target organ or tissue: connective tissues Antinuclear antibodies
o Primarily in skin/ectodermal tissues, but can cause multi-organ
pathology
o Skin fibroblasts reproduce faster and produce more collagen
o CREST form:
C – calcinosis
R – Raynaud’s phenomenon
E – esophageal dysmotility
S – sclerodactyly
T – telangiectasias

Systemic Lupus Erythematosus ANA

o Systemic and multi-organ Anti-ENA
o Immune complexes are formed in the serum Anti-dsDNA antibodies
o Immune complexes are trapped in basement membrane of glomeruli, Anti-phospholipid antibodies
skin/endothelium, synovial joints, kidney Anti-Sm
Anti-DNP

Type I diabetes mellitus Anti-glutamic acid decarboxylase

o Selective destruction of the insulin-producing β cells of the islets of (antibodies to β-islet cells of the
Langerhans in the pancreas pancreas)
o Viruses can trigger autoantibody production by molecular mimicry. Anti-insulin antibodies
After outbreaks of mumps, measles, rubella, Coxsackie B virus, ad
infectious mononucleosis, new cases of type 1 diabetes appear in
communities
o HLA-DQ1.2 and HLA-DR2 decrease the risk of developing diabetes.

Wegener’s granulomatosis Anti-neutrophilic cytoplasmic

o Granulomatous inflammation involving the respiratory tract, and antibodies
necrotizing vasculitis affecting small to medium-sized vessels
(capillaries, venules, arterioles, and arteries)
o Necrotizing glomerulonephritis is common

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 Other Autoimmune Diseases
Disease Target Organ Or Tissue Immunologic Manifestation
Crohn’s disease Intestines Inflammatory infiltrate of T and B
cells; mechanism is unknown

Disseminated encephalomyelitis Central nervous system Sensitized T cells

o It may occur after vaccination (e.g.
rabies immunization) or viral infection
(e.g. measles, influenza).
o The disease represents a cell-mediated
allergic response to myelin basic protein

Guillain-Barre Syndrome Nervous system Sensitized T cells

o This occurs after an infectious disease
(e.g. measles hepatitis) or after
vaccination (e.g. influenza).
o This is a self-limiting paralytic syndrome
that occurs rarely (1 per 100,000
vaccines)

Post-streptococcal glomerulonephritis Kidney Streptococcal antibodies that

cross-reacts with kidney
tissues

Rheumatic fever Heart Streptococcal antibodies that

cross-reacts with heart tissues

Sjogren’s syndrome Eyes, mouth Antinuclear antibodies, RA factor,

o Chronic inflammatory disease that anti-salivary duct antibodies,
affects the exocrine glands (lacrimal and anti-lacrimal gland antibodies
salivary glands)
o Patients have dry eyes
(keratoconjunctivitis sicca) and dry
mouth (xerostomia), dry nose, larynx
and bronchi; little moisture is evident in
the vaginal mucosa
o Patients demonstrate
hypergammaglobulinemia due to
increased B-cell activity

Sarcoidosis Multisystem granulomas Activation of T lymphocytes

o Granulomatous disease Pulmonary manifestations

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 IMMUNOLOGY & SEROLOGY – Immunodeficiency Disorders

Immunodeficiency
➲ Dysfunction in body defense that cause a failure to detect foreign antigens and produce antibodies against these
foreign (non-self) substances

1. Primary Immunodeficiency
a. Humoral Immune Deficiencies
1) Bruton’s X-linked Agammaglobulinemia
➲ X chromosome-linked, affects males spontaneously
➲ Patients lack circulating B cells and exhibit deficiency or lack of immunoglobulin of all classes
➲ A marked deficiency of all classes of immunoglobulins is detected after about 6 months of age
➲ Recurrent, life-threatening infections occur with encapsulated bacteria, such as Streptococcus
pneumoniae and Haemophilus influenzae, manifested as pneumonia, sinusitis, bronchitis, otitis,
furunculosis, meningitis and septicemia
➲ B cells are markedly decreased or absent

2) Transient Hypogammaglobulinemia of Infancy

➲ Infants experience low level of immunoglobulins at approximately 5 to 6 months of age, but in some
babies the low levels persist for a longer time
➲ Cell-mediated immunity is normal and there may be normal levels of IgA and IgM; IgG tends to be the
most affected
➲ Immunoglobulin levels usually normalize spontaneously, usually by 9 to 15 months

3) Common Variable Immunodeficiency

➲ Characterized by hypogammaglobulinemia that leads to recurrent bacterial infections, particularly
sinusitis and pneumonia
➲ There is usually a deficiency of both IgA and IgG, but selective IgG deficiency may occur

4) Hyper-IgM Syndrome
➲ X-linked genetic disease
➲ Serum IgM is increased; IgG and IgA are markedly decreased or absent
➲ A defect in CD40 ligand on T helper cells prevents class switching from IgM to IgG, IgA, or IgE
➲ Affected individuals are prone to respiratory tract infections
➲ Affected individuals often have autoantibodies to platelets, red blood cells and neutrophils

5) Selective IgA Deficiency

➲ Most common congenital immunodeficiency; most patients are asymptomatic
➲ Patients present with small amounts or absence of serum and secretory IgA
➲ Usually caused by a genetic defect or by drugs (phenytoin and penicillin)
➲ Those with symptoms usually have infections of the of the respiratory and gastrointestinal tract and an
increased tendency to autoimmune diseases such as SLE, RA and thyroiditis
➲ Allergic disorders and malignancy are also more common
➲ Anaphylaxis may result if IgA is administered to someone with this deficiency (i.e., blood transfusion)

6) Isolated IgG Subclass Deficiency

➲ Isolated deficiency of any one of the four IgG subclass

Characteristics of Selected Defects of the B Cell System:
Condition Deficiency Level of Defect Presentation
Transient All antibodies, especially Slow development of 2-6 months; resolves by 2
hypogammaglobulinemia IgG T helper function years
in some patients
IgA deficiency IgA, some with reduced IgA B cell Often asymptomatic
IgG2 also differentiation
Bruton’s X-linked All antibodies isotypes Pre- B cell Infancy
agammaglobulinemia reduced differentiation
Common variable Reduced antibody, many B cell Usually 20-30 years of
immunodeficiency different T cell suppression age
combinations
Isolated IgG subclass Reduced IgG1, IgG2, Defect on isotype Variable with the class
deficiency IgG3 or IgG4 differentiation and degree of
deficiency
Immunodeficiency with Reduced IgG, IgA, IgE B cell switching Infancy
hyperimmunoglobulin M with elevated IgM

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 b. Cellular Immune Deficiencies
1) DiGeorge Syndrome (congenital thymic hypoplasia)
➲ Developmental abnormality of the third and fourth pharyngeal pouches that affects thymic
development
➲ Quantitative defect in thymocytes; not enough mature T cells are made but those that are present are
functionally normal
➲ Symptoms include hypocalcemic tetany, due to underdevelopment of the thymus, and heart disease
➲ Immune defect is variable, from slight decrease in T cells to no T cells in the bloodstream
➲ Patients are very susceptible to opportunistic infections and have a poor prognosis

2) Chronic Mucocutaneous Candidiasis

➲ T cells fail to recognize only the Candida antigen

3) Nezelof Syndrome
➲ Cellular immunodeficiency with immunoglobulins
➲ Diminished lymphoid tissue and abnormal thymus morphology
➲ Peripheral lymphoid tissues are hypoplastic and demonstrate paracortical lymphocyte depletion
➲ Serum levels of most of the five immunoglobulin classes are normal or increased

Note: Because T cells are involved in both humoral- and cell-mediated responses, individuals with T helper cell
deficiencies can have severe combined immunodeficiency

c. Combined Deficiencies of Cellular and Humoral Immunity
1) Severe Combined Immune Deficiency (SCID)
➲ A group of diseases, with different causes, that affect T and B cell function, resulting in a suppression of
humoral- and cell-mediated immune responses
➲ Most serious of the congenital immunodeficiencies

2) Enzyme Deficiencies
➲ Defects in adenosine deaminase (ADA) or purine nucleoside phosphorylase (PNP)
• PNP deficiency
o PNP deficiency affects an enzyme involved in the metabolism of purines
o It produces moderate to severe defect in cell-mediated immunity with normal or mildly
impaired immunity
➲ Absence of these enzymes causes an accumulation of nucleotide metabolites in all cells, which is
particularly toxic to T and B cells
➲ Very low number of T cells is present, and children often have underdeveloped thymus, lack of tonsils or
lymph nodes, hypogammaglobulinemia, and lymphopenia

3) Bare Lymphocyte Syndrome

➲ With an MHC class II deficiency, T helper cells fail to develop
• Patients present with hypogammaglobulinemia and no CMI response
➲ MHC class I deficiency is less severe
• There is a loss of cytotoxic T lymphocytes and response to intracellular pathogens

4) Wiskott-Aldrich Syndrome
➲ Mutation in the gene that codes for the Wiskott-Aldrich syndrome protein (WASP), a protein involved
with cytoskeletal reorganization necessary for delivering cytokines
➲ The defect prevents T helper cells from delivering lymphokines to B cells, macrophages, and other target
cells
➲ Patients demonstrate eczema, thrombocytopenic purpura, and increased risk of infection; platelets are
small and defective

5) Ataxia-telangiectasia
➲ Autosomal recessive disorder that presents with ataxia, telangiectasia, recurrent sinopulmonary
infections, a high incidence of malignancy, and variable immune defects
➲ Characterized by cerebellar ataxia and telangiectasias, especially on the earlobes and conjunctiva
➲ Levels of IgG2, IgA and IgE are often low or absent
• Patients typically present with an IgA and sometimes IgE deficiency
➲ It is not primarily an immunodeficiency but a defect in a kinase gene that regulates the cell cycle
o B and T helper cells are affected
• In addition the number of circulating T cells is often decreased

6) Hyperimmunoglobulin E Syndrome
➲ From infancy, patients have histories of staphylococcal abscesses (skins, lungs, joints, and other sites)


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Characteristics of Selected Defects of the T Cell System and Combined Defects:
Condition Deficiency Level of Defect Presentation
DiGeorge anomaly T cell Embryologic defect of the Neonatal: with
Some secondary to thymus hypocalcemia or cardiac
effects on antibody defects if severe;
production incomplete forms may
present later with
infection
PNP deficiency T cells PNP Infancy
Some secondary effects Purine metabolism
on antibody production
SCID Both T and B cells Adenosine deaminase Infancy
(ADA) deficiency
Interleukin secretion or
receptor
HLA expression
Wiskott-Aldrich Reduced IgM and T cell CD43 expression Usually infancy, mild
syndrome defect variants occur
Ataxia telangiectasia Reduced IgG2, IgA, IgE DNA instability Infancy
and T lymphocytes
Reticular dysgenesis All leukocytes
Stem cell defect Neonatal

2. Secondary Immunodeficiency
➲ Acquired; more common
➲ Secondary immune deficiencies are due to an underlying cause
➲ Mainly affect phagocytic and lymphocyte function
➲ Factors affecting secondary immunodeficiencies:
Factor Component Affected
Malnutrition • Protein calorie malnutrition and lack of certain dietary elements (iron,
zinc)
• Major predisposing factor worldwide
Tumors • Direct effect of tumors on the immune system by effects on
immunoregulatory molecules or release of immunosuppressive
molecules
Aging • Increased infections
• Reduced responses to vaccination
• Decreased T and B cell responses
• Changes in the quality of the response
Trauma • Increased infections probably related to release of
immunosuppressive molecules such as glucocorticoids
Other diseases (diabetes mellitus) • Increased susceptibility to infections
Immunosuppression by microbes • Decreased T cell function and antigen processing presentation
(malaria, measles, HIV infections)

➲ Transient hypogammaglobulinemia of infancy presents as a decline in serum immunoglobulins during the first
few months of life. Individuals eventually produce normal amounts of immunoglobulins
➲ Malignancy
• Cancers can exert a suppressive effect on the immune system
• Impairment of antibody production is found in lymphomas, chronic lymphocytic leukemia, and multiple
myeloma
➲ Nutritional deficiencies and defects: malnutrition and protein-energy malnutrition syndromes (e.g., marasmus)
➲ Viral disease: certain viruses impair the function of the immune system
a. Human immunodeficiency virus (HIV)
• Member of family Retroviridae
• HIV causes acquired immunodeficiency syndrome (AIDS)
• There are two serogroups: HIV-1 is the predominant strain, and it is found worldwide. HIV-2 is limited
primarily to West Africa
• HIV-1 has three subtypes: M, N, and O
• Replication:
1) HIV binds to CD4 molecule on T helper cells, monocytes, macrophages and other cells. Secondary
receptors (co-receptors) are also important in viral binding.
2) HIV penetrates the plasma membrane of the cell, and the viral RNA is released
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 3) The RNA is transcribed to DNA by the activity of the viral enzyme reverse transcriptase. Viral DNA is
then inserted into the host cell’s DNA by viral integrase.
4) The viral DNA is transcribed into mRNA, which is then translated into viral proteins. Mature viruses
leave the host cell by budding.
5) The replication process kills the infected cell and leads to a diminishing number of T helper cells.

• Immune response and HIV:

1) Serologic effects
o Antibodies to HIV generally appear about 12 weeks after infection. These are the first antibodies
detected by ELISA and Western blot assays.
o Neutralizing antibodies, antibodies able to interfere with infection of host cells, appear about 1
year after infection. Although these neutralizing antibodies can interfere with viral replication,
they do not seem to play a major role in protection.
o HIV is able to escape the immune response by undergoing antigenic variation
2) Effect on T cells
o As the disease progresses, there is a depletion of CD4+ T helper cells
• The immune deficiency worsens as more T helper cells are killed by the virus
o HIV compromises the immune response by destroying T helper cells
• These cells are key players in both humoral and cellular immune responses
o The ratio of CD4 to CD8 cells is reduced from 2:1 (normal)
3) Additional effects
o Decreased natural killer cell activity
o Defective chemotaxis in monocytes and macrophages
o Enhanced release of interleukin-1 and cachetin by monocytes

• Epidemiology:
o HIV-1 is transmitted by unprotected sex, contaminated blood or blood products, contaminated
needles, or perinatally
o In the US, AIDS is the number one cause of death for people between 20 and 35 years of age

• Symptoms:
o Initially, infected persons (acute phase) will be asymptomatic or can have minor symptoms
resembling infectious mononucleosis
o The virus continues to replicate rapidly in the lymphoid tissue
• This stage is referred to as clinical latency
o As the number of T cells begins to decrease, the patient develops a number of infections caused by
opportunistic pathogens: Candida, herpes simplex virus, cytomegalovirus, etc.
• This stage has been referred to as AIDS-related complex (ARC)
o Final stage (full-blown AIDS) includes T cell depletion resulting in severe opportunistic infections
and cancers, such as esophageal candidiasis, Cryptococcosis, systemic cytomegalovirus and herpes
simplex virus infections, Pneumocystis jiroveci pneumonia, and Kaposi’s sarcoma
o CD4+ T cell counts and presence of a variety of opportunistic infections are used to stage the
severity of the disease

• Laboratory Tests:
o ELISA tests are used to detect antibodies to HIV and HIV antigen
• Repeatedly positive samples must be confirmed by a Western blot or immunofluorescence test
o The Western blot assay is the confirmatory serological test for HIV
• Two of the three bands must appear for p24, gp41, or gp 120/160
o Genetic probes can detect replicating viruses
o Reverse transcriptase-polymerase chain reaction assays detect nucleic acid gene sequences in HIV-1
and HIV-2
o The indirect immunofluorescence assay is used to detect HIV antigen in infected cells
• This can also be used as a confirmatory test

• Therapy:
1) 1987
o Zidovudine (AZT) first nucleoside analog reverse transcriptase inhibitor (NRTI) to be used in HIV
infection
o Others: non-NRTI (NNRTI); protease inhibitors and entry inhibitors
2) 1996
o Combination chemotherapy
o 2 NRTI’s and NNRTI or protease inhibitor: Highly Active Antiretroviral Therapy (HAART)
• Lowering of plasma viral load
• Increase in CD4 cell counts
• Decreased risk of opportunistic infections
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 b. Epstein-Barr virus (EBV)
• DNA virus: member of the herpes virus group
• Transmission is through saliva
• Immunity lasts a lifetime; however, the virus causes latent infections, and infected persons remain
carriers for life
• Serological tests detect heterophile and virus specific antibodies
• Diseases:
1) Infectious mononucleosis
o A disease of reticuloendothelial system
o Incubation period is 4-7 weeks
o Onset may be acute or insidious with sore throat, fever, and lymphadenopathy
o Common findings are lymphocytosis, with many reactive (atypical) lymphocytes, and enlarged
cervical lymph nodes
o Other signs include fever and malaise
o The acute phase lasts 2 weeks and requires a long convalescence, up to 1-2 months
o Infected individuals have abnormal white blood cell differentials and sometimes abnormal liver
function tests
o Infections usually resolve in 4-6 weeks
2) Burkitt’s lymphoma
o Burkitt’s lymphoma is a malignant neoplasm of B lymphocytes
o Found in restricted areas of Africa and New Guinea
o Primarily seen in children
3) Nasopharyngeal carcinoma
o Nasopharyngeal squamous cell carcinoma found mainly in southern China

c. Cytomegalovirus (CMV)
• A herpes family virus that can cause congenital infections in the newborn and a clinical syndrome
resembling infectious mononucleosis

3. Complement Deficiencies
➲ Genetic deficiencies have been described for each of the complement proteins
➲ Homozygous deficiencies in any of the early components of the classical complement proteins result in immune
complex diseases
➲ Patients with defects in early alternative complement proteins, such as factor D and properdin, are susceptible
to infections by Neisseria meningitidis
➲ Patients with C3 defect have the most severe clinical manifestations

4. Defects of Neutrophil Function
a. Chronic Granulomatous Disease (CGD)
• Most common and best characterized of the neutrophil abnormalities
• Genetic defect in any of the several components of the NADPH oxidase system can result in CGD phenotype
by making the neutrophils incapable of generating oxidative burst

b. Leukocyte Adhesion Deficiency (LAD)

• In LAD, a protein (CD18) that is a component of adhesion receptors in neutrophils or monocytes (with CD11b
or CD11c) and on T cells (with CD11a) is defective
• Defect leads to abnormal adhesion, motility, aggregation, chemotaxis and endocytosis of the affected WBCs

c. Chediak-Higashi Syndrome
• Represents a qualitative disorder of neutrophils
• It is a rare familial disorder inherited as an autosomal recessive trait and expressed as an abnormal
granulation of neutrophils
• Neutrophils having giant granules display impaired chemotaxis and delayed killing of ingested bacteria

d. Myeloperoxidase Deficiency
• A deficiency of myeloperoxidase is inherited as an autosomal recessive trait on chromosome 17
• In this disorder, azurophilic granules are present, but myeloperoxidase is decreased or absent
• If phagocytes are deficient in myeloperoxidase, the patient’s phagocytes manifest mild to moderate defect
in bacterial killing and a marked defect in fungal killing in vitro

e. Specific Granule Deficiency

• Caused by failure to synthesize specific granules and some contents of other granules during differentiation
of neutrophils on the bone marrow
• Patients with specific granule deficiency have recurrent, severe bacterial infections of the skin and deep
tissues, with depressed inflammatory response
Lecture Notes in Immunology and Serology Page 11 of 12
Screening Test for Immune Deficiencies:
Suspected Disorder Test
All immunodeficiencies • CBC, WBC differential count

Humoral immunity • Serum IgG, IgA, IgM levels, IgG subclass levels, isohemagglutinin titers (IgM), IgG
antibody response to protein and polysaccharide antigens

Cell-mediated immunity • Delayed hypersensitivity skin tests (i.e., candida, diphtheria, tetanus, PPD)
• Chest X-ray (thymus shadow)

Phagocyte defect • Nitro-blue tetrazolium (NBT) test

• IgE level (hyper-IgE syndrome)

Complement • Hemolytic titration assay/CH50 (classical pathway)

• Serum C3 level

Specialized Confirmatory Test for Immune Deficiencies:
Humoral immunity • B-cell counts (total and IgM, IgD, IgG, IgA-bearing)
• B-cell proliferation in vitro
• Histology of lymphoid tissues

Cell-mediated immunity • T-cell counts (total and helper-suppressor subsets)

• T-cell function in vitro
• Enzyme assays (ADA, PNP)

Phagocyte defect • Leukocyte adhesion molecule analysis (CD11a, CD11b, CD11c, CD18)
• Phagocytosis and bacterial killing assays
• Chemotaxis assay
• Enzyme assays (myeloperoxidase, glucose-6-phosphate dehydrogenase,
components of NADPH oxidase)

Complement • Other specific components

Lecture Notes in Immunology and Serology Page 12 of 12