Kharkiv National Medical University

The immune system

Morphofunctional peculiarities,
methods of examination,
semiology of diseases

Head of the Department of Fundamentals of Paediatrics N2

Klymenko Victoria Anatoliivna

 The function of the immune system

 Providing bodily defense against

infection, autoimmune disease, and
malignancy

 The cost of this protection is allergy,

autoimmune diseases and rejection of
organ transplantations
The organs of immune system

All organs may be divided into

 central organs
 bone marrow
 thymus

 peripheral organs
 spleen
 lymph nodes
 gut-associated lymphoid tissue
(tonsils, Peyer's patches, and
appendix), SALT (skin-…) and other
lymphoid tissue of mucous
membrane
 Bone marrow
is a central organ of
immune system

 Bone marrow contains pluripotent stem cells

which, under the influence of various colony stimulating factors, are
capable of giving rise to all hematopoietic and immune cells
 The first hematopoietic cells appear in bone marrow on the 12-14
th

weeks of gestation.
 From 20 week bone marrow is source of stem cells for myelopoesis

and lymphopoesis

 It is the major site of maturation of B cells, monocytes, and granulocytes

 Mature B lymphocytes, monocytes, and dendritic/Langerhans cells enter

the circulation and home to peripheral lymphoid organs as well as the skin
and mucous membranes and await activation by foreign antigen
 Thymus
is central organ of immune system
 It’s place for differentiation of
T- lymphocytes (thymus -
dependent)

 Stem cells migrating to the

thymus are influenced by
humoral factors, such as
thymosin and thymopoetin

 On leaving the thymus, these

T cells migrate through out
the body and preferentially
seed specific T cell areas
within the lymph nodes,
spleen, appendix, and
intestinal Peyer’s patches.
 Thymus
is central organ of immune system
 Peculiarities of thymus function depends on age
 Thymus is pawned on gestation term near 6 week
 Lymphocytes appear in thymus from 8-9 weeks. They are the first
from a liver and than – from a bone marrow
 Thymus is rather mature organ after birth
 Maturation continues till 12-15 years
 After 15 years function of thymus decreases – it’s called
physiological involution.

Thymomegalia
These conditions


If involution takes place early due to

are dangerous

action of pathological factors (antibiotic,
stress and severe diseases) it’s called
due to formation
of immunological
accidental (convertible) involution.
insufficiency
Peripheral immune system’s organs
(lymph nodes)
 Two types of immunity

The innate


(non-adaptive, non-specific)  The adaptive

immunity (acquired, specific)
immunity

It is formed earlier in
It is characterized by


ontogenesis and provides the antigen-specific
function of protection before responses to a foreign
final maturing more perfect antigen or pathogen
mechanisms

 That is why the innate immune

has great value for fetus and
children of early age
 The innate
(non-adaptive, non-specific)
immunity
The innate immune system consists of
 Natural barriers:  Cellular factors  Humoral (plasma)
Anatomical barriers factors
Macrophages


(skin, mucous membranes)
 Precursors of Complement

 Mechanical removal dendritic cells or system

(a cough, a diarrhea, a immature System of blood
vomiting, the discharging
of an urine, a sweat, a dendritic cells coagulation
saliva, a tear)  Natural killer (plasma factors)
(NK) cells Properdini
 Biochemical barriers
(lisocyme, acidity of  Neutrophils Acute phase

stomach juice, fat acids  Eosinophils proteins (C –

of sebaceous glands, reactive protein)
biochemical changes due  Mast cells and
to high temperature, the basophils Interferon
hormonal status and
other).  Epithelial cells
 Cells of the innate immune system
and their roles in Innate Immunity
Cell Type Major Role in Innate Immunity
Macrophages Phagocytose and kill bacteria; produce antimicrobial
peptides; produce inflammatory cytokines
Dendritic cells Produce large amounts of interferon (IFN), which has
antitumor and antiviral activity
Natural killer (NK) cells Kill foreign and host affected cells
NK-T cells Lymphocytes with both T cell and NK surface markers
that recognize lipid antigens of intracellular bacteria such
as M. tuberculosis and kill host cells infected with
intracellular bacteria.
Neutrophils Phagocytose and kill bacteria, produce antimicrobial
peptides
Eosinophils Kill invading parasites
Mast cells and basophils Release inflammatory cytokines in response to a variety of
bacteria
Epithelial cells Produce anti-microbial peptides; tissue specific epithelia
produce mediator of local innate immunity
 The innate immune system
Cellular factors
Phagocytosis
 All phagocytes may be divided into two groups:
macrophages (monocytes, NK) and microghages
(neutrophils)

 The stages of phagocytosis:

 Activation as a reply to
occurrence of antigen
 Chemotaxis (a moving to antigen
direction)
 Adhesion (an attachment to an
antigen)
 Absorption of antigen into
cytoplasma forming vacuole
 Lysis (digestion) of antigen.
 The innate immune system
Cellular factors
Phagocytosis
 The peculiarities of phagocytosis in
early-ages children
 Newborn - a function of absorption is

advanced, but a lysis is underdeveloped

 The function of digestion (the maturation of cation

protein in phagocytes) is formed only to 6 months

 Some microbes (Hemophilus influenza, Klebsiella

pneumonia) can not be destroying by phagocytes in
early aged children. Other microbes (Staphylococci,
Gonococci) keep an ability to multiply in protoplasma
of phagocytes and cause the destroying of
phagocytes
 The innate immune system
Humoral factors
The complement system
 is a series of plasma enzymes, regulatory proteins, that
are activated in a cascading fashion
 Function –
 cell lysis

 mastcells degranulation

 chemoattractant for neutrophils and monocytes-macro

phages
 There are two arms of the complement system activation

 Classic pathway –
activated by interaction
of antigen and antibody  Alternative pathway –
to form immune recognizing of a bacteria
complexes surface antigen
The innate immune system
Humoral factors
The complement system
 The adaptive immune system

 is characterized by antigen-specific responses to an antigen

 generally takes several days or longer to materialize,
compared to innate immunity which occurs immediately
 A key feature of adaptive immunity is memory for the
antigen such that subsequent antigen exposures lead to
more rapid and often more vigorous immune responses
 The adaptive immune system consists of

 Cellular  Humoral
T lymphocytes B lymphocytes
 The adaptive immune system
Cellular immunity (T –cells)
 The pool T cells is established in the thymus early in life and is
maintained throughout life both by new T cell production in the thymus
and by antigen-driven expansion of virgin peripheral T cells into
"memory" T cells that reside in peripheral lymphoid organs
 Surface markers of T cells – CD3, CD4, and CD8.
 In lymph nodes, T cells occupy deep paracortical areas around B cell
germinal centres, and in the spleen, they are located in periarteriolar
areas of white pulp.

 Function:
 CD8+ cytotoxic T cells capable of lysis of virus-infected or foreign
cells

 CD4+ T cells- helper are also the primary regulatory cells of T and B
lymphocyte and monocyte function by the production of cytokines
and by direct cell contact. CD4+ have an important role in activation
of B cells and induction of Ig isotype switching
 The adaptive immune system
Humoral immunity (B cells)
 Mature B cells comprise 10 to 15% of human peripheral blood
lymphocytes

 Markers B cells - CD19, CD20, CD21

 Activation markers B cells - CD80

 B cells express on their surface intramembrane

immunoglobulin (Ig) molecules that function as receptors

 The primary function of B cells is to produce antibodies

(immunoglobulins)
 Immunoglobulins

 Immunoglobulins are the products of

differentiated B cells and mediate
the humeral arm of the immune response

 The primary functions of antibodies are to bind specifically to antigen and

bring about the inactivation or removal of the antigen from the organism

 All immunoglobulins have the basic structure of two

heavy and two light chains. Immunoglobulin isotype (i.e.,
G, M, A, D, E) is determined by the type of Ig heavy
chain present.
IgG and IgA isotypes can be divided further into
subclasses (G1, G2, G3, G4, and A1, A2) based on
specific antigenic determinants on Ig heavy chains.
 Immunoglobulin A

 IgA comprises only 7 to 15% of total serum immunoglobulin

 It is the predominant class of immunoglobulin in secretions (tears, saliva, nasal

secretions, gastrointestinal tract fluid, and human milk)

 IgA is in the form of secretory IgA (sIgA), a polymer consisting of two

monomers in secretions

 IgA fixes complement via the alternative complement pathway and has potent
antiviral activity in humans by prevention of virus binding to respiratory and
gastrointestinal epithelial cells

 IgA may be synthesized from 7 month of gestation

 IgA is the second largest group of immunoglobulins and it cannot cross the
placenta

 Its presence in human breast milk lowers the incidence of enteric infections in
breastfed infants
 Immunoglobulin M
 IgM is the first immunoglobulin to appear in the immune response
(primary antibody response)

 It is the initial type of antibody made by neonates

 IgM may be synthesized from 3 month of gestation

 IgM antibody binds the C1 component of complement - activator of the

complement cascade

 The IgM molecule is the largest of all the immunoglobulin therefore it

cannot cross the placenta.
 The examination of cord blood for IgM levels can reveal the existence of the
congenital infection. This is commonly part of the initial newborn screening
for the TORCH diseases (Toxoplasmosis, Rubella, Cytomegalic inclusion
disease, and Herpes).

 IgM level is low in newborns

 Reaches the level of adults till 4-5 yrs.
 Immunoglobulin G

 IgG comprises approximately 75 to 85% of total serum Igs

 IgG antibodies are frequently the predominant antibody made after

rechallenge of the host with antigen (secondary antibody response)

 Ig G may be synthesized from 5 month of gestation. But fetus is in

sterile condition that is why levels of all own Igs aren’t high.

 Maternal IgG is actively transported across the placenta. Maternal IgG

provides passively immunity against generalized infection

 Blood group antibodies are also in the IgG class, and therefore can
freely cross the placenta to cause hemolytic disease of the newborn

 During first 3-6 months maternal IgG has been destroying but level of
own Igs is not high enough – it’s physiological hypoimmune condition.
 IgG reaches the level of adults till 5-6 yrs.
 Immunoglobulin E, D

 IgE, which is present in serum in very low concentrations, is

the major class of immunoglobulin involved in activation of
mast cells and basophils. Antigen cross-linking of IgE
molecules on basophil and mast cell surfaces results in
release of mediators of the immediate hypersensitivity
response (allergy, antiparasite responses)

 IgD is found in small quantities in serum. It is a marker for

mature B cells

 Terms of beginning of synthesis IgD and IgE are not clear

exactly
 The clinical examination
 An interrogation (complains, anamnesis morbi, family
anamnesis, pedigree, side effects of vaccination)

 An observation (assessment of physical development,

condition of skin, mucous membranes and skeleton, presents
of ataxia)

 A palpation
 lymph nodes, spleen, liver to reveal pathological symptoms
(infection) from respiratory,
cardiovascular and other systems
 A percussion which can be clinical manifestation of
immune system disorders
 An auscultation
 Paraclinical methods of investigation

 Clinical problems that require an evaluation of immunity

include chronic infections, recurrent infection, unusual
infecting agents, unusual reaction on vaccination, and
certain autoimmune syndromes.

 Clinical assessment of immunity requires investigation of

the four major components of the immune system
 Humoral immunity

 Cell-mediated immunity

 Phagocytosis

 Complement
 Laboratory Evaluation
of Cellular immunity
Quantification of blood cell populations by
immunofluorescence assays employing monoclonal antibody
markers T cells: CD3, CD4, CD8
Activation markers T cells - CD154
T cell functional evaluation
• Delayed hypersensitivity skin tests
• Proliferative response to mitogens (anti-CD3
antibody, phytohemagglutinin, concanavalin A)
• Cytokine production
 Laboratory Evaluation
of Humoral immunity
Quantification of blood cell populations by
immunofluorescence assays employing monoclonal antibody
markers B cells: CD19, CD20, CD21
Activation markers B cells - CD80
Serum immunoglobulin levels: IgM, IgG, IgA, IgD, IgE
B cell functional evaluation
•Natural or commonly acquired antibodies: isohemagglutinins;
antibodies to common viruses (influenza, rubella) and bacterial toxins
(diphtheria, tetanus)
• Response to immunization with protein (tetanus toxoid) and
carbohydrate (pneumococcal vaccine, H. influenzae B vaccine)
antigens
•Quantitative IgG subclass determinations (G1, G2, G3, G4)
 Laboratory Evaluation
of Phagocytosis and Complement
Quantification of blood cell populations by
immunofluorescence assays employing monoclonal antibody
markers NK cells: CD16/CD56
Monocytes: CD15
Phagocyte function
1. Reduction of nitroblue tetrazolium
2. Chemotaxis assays
3. Bactericidal activity

Complement
1. CH50 assays
2. C3, C4, and other components
 The basic group of diseases with
pathology of immune system
in there pathogenesis

 Primary and Secondary Immunodeficiency

 Infection of the immune system (infection

mononucleosis, AIDS)

 Malignant diseases of immune system

(lymphosacroma, lyphogranulomatosis, lymphoma)

 Disease with autoimmune genesis, allergic

diseases
 Immunodeficiency
Secondary immunodeficiency -
Primary immunodeficiency –  Immunity disorders caused by other
diseases or factors:
due to genetic defect of
 malignant diseases
immune system
 bacterial and virus infection
(AIDS)
 may be manifested clinically
 malnutrition, protein-losing
at once after birth or later
enteropathy
 is divided into 5 groups
 metabolic disorder
depending on the kind of
immune defect;  stress

 Cellular

 Humoral  may be permanent or transient

 Combine  may be divided into 5 groups
 Phagocytes
depending on the kind of immune
cells defect (like primary
 Complement
immunodeficiency)
 Defects in cellular immunity
Clinical manifestation
 Viral infections (predispose to disseminated infections, particularly with
latent viruses such as herpes simplex, varicella zoster, cytomegalovirus)
 Mycobacterial infections
 Fungal infections
 Severe complication (systemic illness) following after vaccination by
alive virus and BCG
 T cell deficiency is always accompanied by some abnormality of antibody
responses, although this may not be reflected by
hypogammaglobulinemia.

Examples of T-cell immunity deficiency:

 Di-George anomaly (DGA) – is caused by an embryologic field defect that
results in thymus abnormalities, heart malformations, facial anomalies,
parathyroid deficiency (convaltion)
 Nezelof syndrome – a cartilage – hair hypoplasia, a bone dysplasia, is associated
with short limbed dwarfism and immune deficiencies
 AIDS - is extreme example of secondary deficiency in cellular immunity
 Defects in humoral immunity

Clinical manifestation
 recurrent or chronic bacterial infections (Sino-pulmonary infection,
otitis, meningitis, and bacteremia), frequently with organisms such as
Streptococci, Haemophilus influenzae, and Staphylococci.

Examples of B-cell immunity deficiency:

 Bruton agammaglobulinemia - X linked – all class of immunoglobulin
deficiency. Recurrence infections are typical for agammaglobulinemia,
but there is no lymphadenopathy or splenomegaly. Skin disorders and
later pulmonary dysfunction are frequent.

 Selective deficiency of immunoglobulin A – is characterized by

recurrent respiratory infections and diarrhea. Autoimmune diseases
are associated with this defect. Many children are asymptomatic.

 Selective deficiency of immunoglobulin M – these patients have a

high risk of rapid hematogenous spread of bacterial infections.
 Combined immunodeficiency
(T and B cell associated deficiency)
 The most severe form of immune deficiency
 Individuals with severe combined immunodeficiency are
susceptible to the whole range of infectious agents
including organisms not ordinarily considered pathogenic.

Examples
 Wiskott-Aldrich syndrome – an X-linked recessive
disorder – thrombocytopenia, otitis, pneumonia and eczema
during the first 6 mo of life. Hepatosplenomegaly and
lymphadenopathy are common. Serum IgG and IgE are
markedly elevated.

 Ataxia-telangiectasia - ataxia, ocular and cutaneous

telangiectasias, chronic sinopulmonary disease, and
endocrine abnormalities, neurological disorder.
 Disorders of phagocytosis
 recurrent skin infections, often due to
Staphylococcus aureus, abscesses of
subcutaneous tissue and lungs, purulent
arthritis and osteomyelitis.

Examples
 Chronic granulomatosis
 Acquired immunodeficiency syndrome
(AIDS)
is the most dangerous disease of an
immune system

 AIDS is now a pandemic

 Every day about 1,000 children under the age of 15 become infected
with HIV
 There were more than 2 million children with HIV now, about 90 %
of them living in Africa

 There are two main definitions for AIDS, both produced by

the Centres for Diosease Control and Prevention(CDC).
 The older definition is to referring to AIDS using the diseases that
were associated with it, for example, lymphoma.

 In 1993, the CDC expanded their definition of AIDS to include all

HIV-positive people with a CD4+ T cell count below 200 per µL of
blood or 14 % of all lymphocytes
 Human immunodeficiency virus
HIV
 HIV is a retrovirus with cytopathic effects
Transmission of HIV is through direct contact of a
mucous membraine or the bloodstream with a HIV-
containing bodily fluid (blood, semen, vaginal fluid, breast
milk).
The mian ways of transmission
Anal, vaginal or oral sex
Blood transfusion
Contaminated needles
Exchange between mother and baby during
pregnancy, childbirth, breast-feeding

 The most prominent effect of HIV virus is T helper cell

suppression and lysis loss of cellular immunity.
 The stages of HIV infection

 Stage I: HIV infection is asymptomatic and not categorized

as AIDS.

 Stage II includes minor mucocutaneous manifestations and

recurrent infections of the upper respiratory tract.

 Stage III includes unexplained chronic diarrhoea for longer

than a month, severe bacterial infections and pulmonary
tuberculosis.

 Stage IV includes toxoplasmosis of the brain, candidiasis of

the esophagus, trachea, bronchi or lungs and Kaposi’s
sarcoma; these diseases are indicators of AIDS.