COURSE TITLE: IMMUNOLOGY/ IMMUNOCHEMISTRY (3 UNITS)

2019/2020 Second Semester

Module 3_Lecture 1: Immunoglobulins- 24/04/2020 (2hours)
Lecturer: Dr. O. Oduwole

• Structure of the immunoglobulins and infection

Basic structure:
Immunoglobulins: Are antibodies made up of glycoproteins. They are made by activated B-
cells called plasma protein cells.
• Every immunoglobulin molecule has a fundamentally similar structure made up of two
identical 'heavy' polypeptide chains attached to a pair of identical n light chains.
• The light chains have variable regions (VL) and constant regions (CL)) and the same
applies to the heavy chains (variable (VH) and constant regions (CH).
• The variable region of the heavy chain is about the same length as the variable region of
the light chain while the constant region (C H) of the heavy chain is about three times
longer than the length of the (CL).
• There are five classes of the immunoglobulins: These are IgG, IgM. IgA, IgD, IgE
Fig 1: Basic four-chain (H2L2) structure of immunoglobulins. The molecule is usually represented in the form of a Y with the
amino (N-)termini of the four chains at the top and the carboxyl (C-) termini of the heavy chains at the bottom
Mansel Haeney, introduction to clinical immunology(1985)

An antibody molecule has two main functions:

• 1) Antigen recognition (2) Antigen elimination through participation in effector
mechanisms.
• These functions are performed by different regions of the molecule.
• Two of the fragments are identical, each containing one site capable of specific
combination with antigen.
• These antigen-binding fragments (Fab) consist of the entire light chain, the VH region
and part of the CH region.
• The third fragment is composed of the C-terminal halves of the heavy chains but does not
combine with antigen.
• This crystalizable fragment (Fc) mediates the effector functions of an immunoglobulin
which has combined with specific antigen via its Fab regions.
Fig 2: Immunoglobulin fragments produced by papain digestion. The antigen-binding site is contained within the Fab
region and formed by the variable regions of one heavy and one light chain. Each monomeric immunoglobulin possesses
two antigen-binding sites per molecule
Mansel Haeney, introduction to clinical immunology (1985)

Immunoglobulins and infection:

✓ Antibodies are substances made by the body’s immune system to protect it from
infectious agents and foreign antigens such as allergens, fungus, cancer cells etc.
✓ These antibodies attach to the foreign substances so that the immune system can
destroy them.
✓ IgG is the most common antibody in the body and protects the body from invading
microorganisms. For instance, when IgG was given to patients with
hypogammaglobulinemia, their risk of infections was reduced.
✓ Antibodies are specific in their actions. That is, there is an antibody specific for each
foreign substance. E.g. antibodies secreted to fight tubercle bacilli will attach only to
the bacteria.
✓ Antibodies can also be produced specifically against allergens this is what happens in
allergic reaction.
✓ Sometimes, antibodies may be made against ‘self tissue’, this condition is called
autoimmune diseases.
✓ In some individuals. Their immune systems produce low levels of antibodies, as a
results they are constantly at risk of infections repeatedly. Some people are born with
this condition and as a result of immunocompromised conditions like cancer and HIV.
Studies have shown that low serum level of immunoglobulins are associated with
heightened risk of infection as in immunocompromised patients (Furst, 2009).

• Abnormalities of immunoglobulins
1) Concept of polyclonality and monoclonality-

▪ Polyclonal antibodies: are a collection of immunoglobulins (antibodies) that are produced

by different B-cell lineage or ancestry within the body.
▪ Monoclonal antibodies are secreted by a single cell lineage.
▪ Each immunoglobulin is the product of a single family (monoclonal) or clone of plasma
cells (polyclonal). Many different clones are involved in the specific antibody response
but only one clone will synthesize and secrete a particular VH and VL region.
▪ The malignant proliferation of a clone of plasma cells results in the increased production
of immunoglobulin molecules of identical class, subclass, VH and VL regions. Such
monoclonal immunoglobulins have a unique amino acid sequence and a finite
electrophoretic mobility (limited mobility).

2) Polyclonal hyperimmunoglobulinaemia: (Significance of raised serum

immunoglobulin levels)

▪ Raised serum immunoglobulins when considered in conjunction with other laboratory

findings, they may help to distinguish between diseases with otherwise similar clinical
features.
 3) Immunoglobulin patterns in disease:
Infection:
▪ Acute viral infections such as infectious mononucleosis (glandular fever also known as
kissing diseases, it is causes by Epstein Barr virus) and hepatitis stimulate the secretion of
IgM as primary response to the invading infectious agents.
▪ Chronic respiratory or gastrointestinal infections, particularly of mycobacterial or fungal
origin, stimulate a marked increase in both IgG and IgA.
▪ Long-standing bacterial infections, for example subacute bacterial endocarditis or these
are associated with significant elevations of all immunoglobulin classes.

4) Hepatic and gastrointestinal disease

▪ Serum immunoglobulin levels can be of value in liver disease, particularly when
considered with the auto-antibody pattern.
▪ In contrast, patients with inflammatory bowel disease rarely show significant alterations
in immunoglobulin levels, although a minor elevation of IgA sometimes occurs.
▪ A persistently raised IgA is frequently a feature of gluten-sensitive enteropathy and
occasionally of cow's-milk-protein intolerance. Dietary restriction of the offending
antigen is usually accompanied by a fall in serum IgA, but some patients with intestinal
lymphoma complicating coeliac disease show rising IgA levels despite strict dietary
control.
5) Rheumatic diseases
▪ Total immunoglobulin and IgG levels may be moderately raised in seropositive
rheumatoid disease.
▪ Sometimes, elevation of IgA is found in both seropositive and seronegative subjects but
IgM levels are usually normal, irrespective of rheumatoid factor activity.
▪ In a few patients rheumatoid arthritis is associated with selective IgA deficiency. In
active systemic lupus erythematosus (SLE), very high IgG levels may be produced.

6) Immunoglobulin levels in cerebrospinal fluid

▪ Significant changes in serum immunoglobulin levels seldom occur in diseases of the
nervous system.
▪ In contrast, cerebrospinal fluid (CSF) IgG estimation may be of considerable diagnostic
value.
▪ In most inflammatory diseases of the central nervous system, the integrity of the blood-
brain barrier is compromised; serum leaks' into CSF and both CSF IgG and albumin
concentrations show a proportionate increase.

TABLE 1 RAISED SERUM IMMUNOGLOBULINS: COMMON PATTERNS IN

 DISEASE

iMmunoglobul

IgG IgA IgM Typical examples

X Acute viral infection

Hepatitis A
Infectious mononucleosis

Primary biliary cirrhosis

X Acute respiratory or intestinal infection

Coeliac disease

X Autoimmune disease
SLE
Chronic active hepatitis
Hashimoto's thyroiditis

X X Chronic respiratory disease

Tuberculosis
Extrinsic allergic alveolitis
Cystic fibrosis
Portal cirrhosis
Leprosy

X X Chronic bacterial infection

Subacute bacterial endocarditis
Subphrenic abscess
Osteomyelitis
Empyema
Neutrophil dysfunction

7) IgD and disease

▪ No clear evidence exists of a biological role for circulating IgD, the clinical significance
of serum IgD levels in disease is therefore uncertain.
▪ Many healthy people have barely detectable levels and there is little diagnostic
information to be obtained from measurement of serum IgD concentration other than in
cases of IgD myeloma.

Immunoglobulin levels and age

Serum immunoglobulin levels are fairly constant in healthy adults but the development of adult
levels from birth shows a characteristic trend for each immunoglobulin.
 ▪ Only IgG can cross the placenta; although transfer of maternal IgG to the fetus begins as
early as the thirteenth week of pregnancy, maximum transfer takes place in the last
trimester. Premature infants therefore have low IgG levels and show marked
susceptibility to infection.
▪ At birth, the circulating serum IgG is wholly from the mother.
▪ Although adult levels of Igs are reached by the age of 2 years the period between 3 and 6
months is a phase of relative antibody deficiency ('physiological trough').
▪ Placental transfer of IgM is negligible, but fetal production of specific IgM rises to very
high levels in intrauterine infection and may be of diagnostic significance.
▪ In normal infants, the serum IgM level rises rapidly in the first few months of life,
reaching the adult range at between 6 months and 1 year.
▪ IgA is not detectable in cord blood. Its appearance in serum and secretions is more
gradual than IgG or IgM and adult levels are not achieved until adolescence.
▪ IgE does not cross the placenta. Serum levels follow a similar course to IgA, adult levels
being reached at between 7 and 9 years.

Sourse:

1) Mansel Haeney, 'Introduction to clinical immunology’, London Butterworths 1985

2) Roitt's Essential Immunology. Thirteenth Edition. Peter J. Delves, Seamus J. Martin, Dennis R.
Burton, Ivan M. Roitt. 13th edition. | Chichester, West Sussex ; Hoboken, [NJ] : John Wiley
& Sons, Inc., 2017.
3) Furst D.E. Serum immunoglobulin and risk of infection:How low can you go: Semin
Arthritis Rheum, 2009;39(1):18-29.