Immunodeficiencies

Dr. Alfred Ehiaghe

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Immunodeficiencies – major clinical features

• Antibodies - microbial infections (encapsulated bacteria)

respiratory - pneumonia, sinusitis, otitis

GIT – diarrhea
• Complement system – microbial infections (pyogenic), sepsis
edema (HAE) – C1-INH deficiency
• T lymphocytes - bacterial, fungal, viral
GIT – diarrhoea
respiratory – pneumonia, sinusitis
• Phagocytes - abscesses, recurrent purulent skin infections
granulomatous inflammation
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I. Primary immunodeficiencies – phagocytic cell
defects

1/ Quantitative – decreased numbers of granulocytes

Congenital chronic agranulocytosis

Cyclic agranulocytosis (neutropenia)

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I. Primary immunodeficiencies – phagocytic cell
defects
2/ Qualitative – phagocytes functional disorders, various enzyme deficits,
inability of phagocytes to degrade the ingested material

a/ Chronic Granulomatous Disease (CGD)

• Approximately in 60% X-linked
• Enzymatic inability to generate toxic oxygen metabolites (H2O2) during
oxygen consumption) - defect in neutrophilic cytochrome b (part of complex
containing NADPH oxidase)
• Inability to kill catalase producing bacteria such as Staph.aureus,
Pseud.aeruginosa
• Clinical features: granulomas of skin, organs

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 II. Primary immunodeficiencies –
B cell disorders
X-linked hypogamaglobulinemia (XLA, Bruton’s agammaglobulinemia)
• Most common X-linked form
• Block of maturation of pre-B lymphocytes into B lymphocytes (Bruton’s
tyrosine kinase defect)
• Undetectable or very low serum levels of Ig, absence of B cells
• Symptoms: pneumonias, pyogenic otitis, increased occurrence of pulmonary
fibrosis
• Treatment: life-long Ig replacement

CVID – Common Variable ImmunoDeficiency

• Heterogenous group of B cell functional defects
• Low levels of IgG and IgA, B cell counts normal
• Symptoms: onset mostly between 2nd and 3rd decade
recurrent respiratory tract infections (pneumonia, sinusitis)
• Treatment: life-long Ig replacement

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II. Primary immunodeficiencies –
B cell disorders
Selective IgA deficiency
• Disorder of B cell function: absence of IgA, levels of the other Ig normal
• Recurrent mild/moderate infections or asymptomatic
• Risk of reaction to live attenuated vaccines or generation of anti-IgA
antibodies after blood transfusion

Selective IgG subclasses deficiency, specific IgG deficiency

• B cell functional disorder
• Onset of symptoms in childhood, mostly respiratory tract infections
caused by encapsulated bacteria (H.influenzae, Pneumococci)

Transitory hypogammaglobulinemia of infancy

• Milder and transitory decrease of IgG and IgA

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III. Primary immunodeficiencies –
T cell disorders

diGeorge syndrome
• Disorder of development of 3rd and 4th branchial
pouch → congenital heart disease + absence of
thymus + absence of parathyroid glands
• Complete or parcial
• Symptoms: symptoms of cong.heart dis. – prominent
immunodeficency – variable (mild
functional → absence of T cells)
hypocalcemic spasms – possible
mental deficit

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 IV. Primary immunodeficiencies –
combined defects of T and B cells
SCID – Severe Combined ImmunoDeficiency
• X-linked recessive.

• combined disorder of humoral and cell mediated immunity

• Severe disorder (patients often die during until 2nd year of age),
onset of symptoms soon after birth (severe diarrhoea,
pneumonia, meningitis
• Immunological features: typically lymphopenia, absence of T
cells, hypogammaglobulinemia

• Forms: X-linked form – the most common, T-B+NK-, defect of

common gamma chain shared by receptors of various
important cytokines → absence of T cells 8
V. Primary immunodeficiencies –
complement system disorders

Hereditary angioedema (HAE)

• Absence or functional defect of C1-inhibitor

• Recurrent swellings of skin or mucosa (oropharynx, gut) triggered by
intercurrent infect, trauma or surgery
• Uncontroled activation of kinin system
• Laryngeal edemas could be life-threatening, immediate treatment is
necessary

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 Secondary immunodeficiencies

• Acute and chronic viral infections – infectious mononucleosis, influenza

• Metabolic disorders – diabetes mellitus, uremia
• Autoimmune diseases – autoantibodies against immunocompetent cells
(neutrophils, lymphocytes); autoimmune phenomena also after
administration of certain drugs (e.g. oxacilin, quinidine)
• Chronic GIT diseases
• Malignant diseases (leukemia)
• Hypersplenism/asplenia
• Burn, postoperative status, injuries
• Severe nutritional disorders
• Chronic infections
• Ionizing radiation
• Drug induced immunodeficiencies (chemotherapy)
• Immunosupressive therapy
• Chronic stress
• Chronic exposure to harmful chemical substances

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Acquired ImmunoDeficiency Syndrome (A.I.D.S.)

• Caused by retrovirus HIV 1 or HIV 2

• Virus has a tropism for cells bearing CD4 surface marker (Th CD4+
lymphocytes); also infects macrophages and CNS cells
• Viral genome transcribes into human DNA and infected cell provides viral
replication
• Diagnosis: serological (3 to 6 weeks after primoinfection, PCR
• Transmission: sexual contact
contact with blood or blood products
mother-to-child – prenatally, delivery, breast feeding
• Phases: acute (flu-like symptoms)
asymptomatic – months to years, viral replication, loss of Th cells
symptomatic – infections, autoimmune disorders, malignancies,

allergy
final – systemic breakdown, opportune infections (Pneumocystis
jirovecii, Cryptococcus neoformans, Toxoplasma gondii,
Candida albicans, CMV etc.)
- Kaposi’s sarcoma 11
 A.I.D.S. - Treatment

• Reverse transcriptase inhibitors (e.g.zidovudine)

• Protease inhibitors - block the viral protease enzyme
• Combined drug therapy
• Antimicrobial agents

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AUTOIMMUNE DISEASES

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 Autoimmune disease
• Results from a failure of self-tolerance
• Immunological tolerance is specific
unresponsiveness to an antigen
• All individuals are tolerant of their own (self)
antigens

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 AUTOIMMUNE PATOLOGICAL RESPONSE-
ETIOLOGY
• the diseases are chronic and usually irreversible
• incidence: 5%-7% of population, higher frequencies in
women, increases with age
• factors contribute to autoimmunity:

- internal (HLA association, polymorphism of cytokine genes,

defect in genes regulating apoptosis, polymorphism in genes
for TCR a H immunoglobulin chains, association with
immunodeficiency, hormonal factors)
- external (infection, stress by activation of neuroendocrine
axis and hormonal dysbalance, drug and ionization through
modification of autoantigens)

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 CLINICAL CATEGORIES
• systemic
- affect many organs and tissue

• organoleptic
- affect predominantly one organ accompanied
by affection of other organs (inflammatory bowel
diseases, celiac disease, AI hepatitis, pulmonary
fibrosis)

• organ specific
- affect one organ or group of organs connected
with development or function

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 SYSTEMIC AUTOIMMUNE DISEASES

• Systemic lupus erythematosus

• Rheumathoid arthritis
• Sjögren‘s syndrome
• Dermatopolymyositis
• Systemic sclerosis
• Mixed connective tissue disease
• Vasculitis

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 SYSTEMIC LUPUS ERYTHEMATOSUS
• chronic, inflammatory, multiorgan disorder

• autoantibodies react with nuclear material and attack cell

function, immune complexes with dsDNA deposit in the
tissue

• general symptoms: include malaise, fever, weight loss

• multiple tissue are involved including the skin, mucosa,
kidney, joints, brain and cardiovascular system

• characteristic features: butterfly rash, renal involvement,

CNS manifestation, pulmonary fibrosis

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 DIAGNOSTIC TESTS

• a elevated ESR (erythrocyte sedimentation rate), low CRP,

trombocytopenia, leucopenia, hemolytic anemia, decreased
levels of complement compounds (C4, C3), elevated serum Ig
levels, immune complexes in serum

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 AUTOANTIBODIES

• Autoantibodies: ANA, dsDNA (double-stranded),

ENA (SS-A/Ro, SS-A/La), Sm, against histones,
phospholipids

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 RHEUMATOID ARTHRITIS
• chronic, inflammatory disease with systemic involvement
• characterized by an inflammatory joint lesion in the synovial membrane,
destruction of the cartilage and bone, results in the joint deformation
• clinical features: arthritis, fever, fatigue, weakness, weight loss
• systemic features: vasculitis, pericarditis, uveitis, nodules under skin,
intersticial pulmonary fibrosis
• diagnostic tests: elevated C- reactive protein
and ESR, elevated serum gammaglobulin levels
- autoantibodies against IgG = rheumatoid factor
(RF), a-CCP (cyclic citrulline peptid), ANA
- X-rays of hands and legs- show a periarticular
porosis, marginal erosion

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 SJÖGREN‘S SYNDROME

• chronic inflammatory disease affecting exocrine glands

• the primary targets are the lacrimal and salivary gland duct epithelium
• general features: malaise, weakness, fever
• primary syndrome - features: dry eyes and dry mouth, swollen salivary
glands, dryness of the nose, larynx, bronchi and vaginal mucosa,
involvement kidney, central and periferal nervous system, arthritis

• secondary syndrome – is associated with others AI diseases (SLE, RA,

sclerodermia, polymyositis, primary biliary cirhosis,AI thyroiditis)

• autoantibodies against ENA (SS-A, SS-B),

ANA, RF
• The Schirmer test - measures the production
of tears

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 Vasculitis
• characterized by inflammatory destruction
of vessels leading to thrombosis and aneurysms
• proliferation of the intimal part of blood-vessel wall
and fibrinoid necrosis
• affect mostly lung, kidneys, skin

• diagnostic tests: elevated ESR, CRP, leucocytosis,

biopsy of affected organ (necrosis, granulomas),
angiography

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 Vasculitis

• p- ANCA (myeloperoxidase) positivity (Polyarteritis nodosa,

Churg- Strauss, Microscopic polyarteritis nodosa)

• c- ANCA (serin proteinase) positive (Wegener

granulomatosis, Churg- Strauss syndrome)

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 Vasculitis - classification
• Large vessel vasculitis (Takayasu arteritis, Giant cell
(temporal) arteritis)
• Medium vessel vasculitis (Polyarteritis nodosa,
Wegener's granulomatosis, Kawasaki disease)
• Small vessel vasculitis (Churg-Strauss arteritis,
Microscopic polyarteritis, Henoch-Schönlein purpura)
• Symptoms: fatigue, weakness, fever, arthralgias,
abdominal pain, hypertension, renal insufficiency,
and neurologic dysfunction

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ORGANOLEPTIC AUTOIMMUNE DISEASES

• Ulcerative colitis
• Crohn‘s disease
• Autoimmune hepatitis
• Primary biliary cirhosis
• Pulmonary fibrosis

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 Ulcerative colitis

• chronic inflammation of the large intestine mucosa

and submucosa
• features: diarrhea, bloody and mucus stools
• extraintestinal features (arthritis, uveitis)
• Autoantibodies: pANCA, a- large intestine

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 Crohn‘s disease

• the granulomatous inflammation of whole

intestinal wall with ulceration and scarring that
can result in abscess and fistula formation
• the inflammation of Crohn's disease the most
commonly affects the terminal ileum, presents
with diarrhea and is accompanied by
extraintestinal features - iridocyclitis, uveitis,
artritis, spondylitis
• antibodies against Saccharomyces cerevisiae
(ASCA), a- pancreas

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 AUTOIMMUNE ENDOCRINOPATHY

• Hashimoto‘s thyroiditis
• Graves-Basedow disease
• Diabetes mellitus I. type
• Addison‘s disease
• Autoimmune polyglandular syndrome

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 Hashimoto‘s thyroiditis

• thyroid disease result to hypothyroidism on the base

of lymphocytes and plasma cells infiltrate

• autoantibodies against thyroidal peroxidase (a-TPO)

and/or against thyroglobulinu (a-TG)

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 Grave‘s disease

• thyrotoxicosis from overproduction of thyroid

hormone (patient exhibit fatigue, nervousness,
increased sweating, palpitations, weight loss,
exophtalmus)

• autoantibodies against thyrotropin receptor,

autoantibodies cause thyroid cells proliferation

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 Diabetes mellitus (insulin- dependent)

• characterized by an inability to process sugars in the

diet, due to a decrease in or total absence of insulin
production
• results from immunologic destruction of the insuline-
producing β-cells of the islets of Langerhans in the
pancreas
• autoantibodies against GAD (glutamic acid
decarboxylase = primary antigen), autoantibodies
anti- islet cell, anti- insulin
• islets are infiltrated with B and T cells

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 AUTOIMMUNE NEUROPATHY

• Guillain-Barré syndrome (acute idiopathic

polyneuritis)

• Myasthenia gravis

• Multiple sclerosis

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 Multiple sclerosis

• chronic demyelinizing disease with abnormal reaction T cells to

myeline protein on the base of mimicry between a virus and
myeline protein
• features: weakness, ataxia, impaired vision, urinary bladder
dysfunction, paresthesias, mental abberations
• autoantibodies against MOG (myelin-oligodendrocyte
glycoprotein)
• Magnetic resonance imaging of the brain and spine shows
areas of demyelination

• The cerebrospinal fluid is tested for oligoclonal bands, can

provide evidence of chronic inflammation of the central
nervous system
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 AUTOIMMUNE CYTOPENIA

• AI hemolytic disease- autoantibodies against

membrane erythrocyte antigens

• AI trombocytopenia - autoantibodies against

trombocyte antigens (GPIIb/IIIa)

• AI neutropenia - autoantibodies against

membrane neutrofil antigens

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