Immunoglobulin Deficiency: Types And Causes

Both an excess and a deficiency of immunoglobulins, in general or a certain class, can be a sign of various diseases, therefore, determining their concentration is an important, and sometimes the earliest stage of diagnostic measures, which allows you to establish the type of pathogen in time, and, therefore, prescribe the correct one. treatment.

The structure of antibodies

All immunoglobulins contain in their structure two types of chains interconnected by chemical (disulfide) bonds: heavy (or H-) and light (L-) - and it is the variations of the former that contribute to the division of antibodies into classes. A specific combination of individual sections of the chains, folded into balls-globules - domains - leads to the formation of the so-called paratope or antigen-binding center - a key structure, which, in essence, ensures the creation of the "antibody-foreign agent" complex.

In addition, each immunoglobulin has fragments that facilitate its binding to macrophages - such "scavenger cells" that swallow and devour microbial bacteria. This once again speaks of the inseparability of the two links of immunity: cellular and humoral. By the way, another indisputable evidence in favor of this important for understanding the nature of the immune response and the mechanisms of its implementation is the fact that some classes of antibodies can act as facilitators of the previously mentioned phagocytosis process.

It is also noteworthy that antibodies, the producers of which - plasmocytes - are the last of all police defenders to reach the focus of inflammation - circulate not only in the blood, but are also found in some secrets secreted by the human body. We are talking about secretory forms - which, in particular, has a representative of such a class as immunoglobulin A, which is found, say, in the composition of the components of the lacrimal fluid, and also provides protection to the epithelial cells of the gastrointestinal tract. The existence of such a form requires not only a certain rearrangement in the “original” antibody molecule, but also the presence of an additional (except for standard light and heavy) chains.

The mechanism of antibody formation

The producers of antibodies, as already mentioned, are plasma cells - the end products of the development (differentiation) of B-lymphocytes, which are normally formed in the red bone marrow, like other blood cells, and then sent for a kind of training abroad - to such organs as spleen and lymph nodes. Here, at school desks and under the supervision of experienced teachers, they undergo serious training, the purpose of which is to form a clear and final understanding of what is “ours” and what is “alien” and is subject to destruction.

The final final exam is harsh - the judges cannot be bribed, and the slightest glitch in the program immediately leads to inactivation by death sentence of the "wrong" clone. Such a clear regulation of the rules has very impressive reasons: after all, if a cell that has gone crazy and escaped from general control begins to form similar bullets and arrows against the tissues of its own body, real confusion and chaos will begin, as the autoimmune process usually appears.

It is precisely due to the existence of such limiting barriers - there are only five of them - that during embryonic development the immune system is deprived of the opportunity to get acquainted with the antigens of the "beyond the barrier" organs - thus, when faced with them in one or another pathology, it, without any hesitation, regards them as alien and, therefore, uses its impressive armature - in particular, antibody production. There is a violation of natural immunological tolerance.

However, neither B-lymphocytes nor their mature forms - plasmocytes - are able to independently activate upon contact with most pathogenic agents (although there are rare exceptions) - for this they need a stimulating signal from T-cells: such a kick to action, carried out at the molecular and cellular level. T-helpers, a motley population of the previously mentioned type of lymphocytes, provide them with such an opportunity: they, secreting certain molecules, are torn by an alarm siren.

However, if the process itself ended at this stage, it would be boring and, in a way, primitive. However, nature is still a magician. T-helpers are intermediaries that only convey the information they heard about a sudden invasion: they themselves do not fight enemies and do not torture scouts. Their only task is to recognize and report to higher management.

So, let's go in order. A foreign substance enters the body in some way, which, depending on the state of immunity and other functional systems, is intercepted and absorbed by a macrophage police officer at one of the customs borders - it will remain in it until further proceedings in the courtroom and the issuance of a final and impartial verdict . The “devouring” of violators of the order leads to some changes in the structure of their overseer - in particular, on its surface it expresses certain protein complexes, which will represent representatives of certain populations of T-lymphocytes (or rather, their receptors) particles of a foreign antigen. Further, through complex cascade mechanisms for transmitting various kinds of signals, the enemy will be recognized and the battle tactics will be chosen:

Classification of antibodies

1. Depending on the temperature at which immunoglobulins form complexes with an antigen - a substance foreign to a given particular organism - all antibodies can be divided into two groups:

   • Thermal - "glue" the antigen at body temperature - that is, at 37 degrees;

   • Cold - interact with antigens, on average, at +4.

    

2. Based on the ability to form a large (macromolecular) structure, entering into an interaction reaction with a pathogenic agent, immunoglobulins are complete and incomplete.

1. The main, most commonly used classification of immunoglobulins is based on what type of heavy chain underlies their nature. So, there are 5 classes:

• Immunoglobulins M (IgM) - are formed at the time of the first meeting of immunocompetent cells with antigens. This process is quite long and is characterized by an impressive latent phase - for example, diagnostically significant antibody titers appear only by the 2nd week of the disease - on average, on the 10-14th day.

  So, this class of antibodies is a kind of pioneers who happen to get acquainted with unwanted guests and, only after not the most rosy tea party, switch antibody production to the synthesis of their somewhat different counterparts.

   

• Immunoglobulins G - it is they that account for most of the antibodies in the blood serum (up to 80%). With their small size and low molecular weight, they are the only class of antibodies that passes through the placental barrier and thus provides the natural passive immunity of the fetus - however, it lasts no more than six months.

In general, the inability of most immunoglobulins to overcome this barrier, which clearly demarcates the blood of the mother and the fetus, plays a double role - both positive and negative. So, say, one of the leading causes of meningitis, inflammation of the membranes of the brain of a bacterial nature, which is caused by some opportunistic strains of Escherichia coli, is associated precisely with the impregnability of the customs border in the form of the placenta for the bulk of antibodies.

As mentioned earlier, during the initial contact with a foreign substance, at the antibody production factory, the launch of batch formation of IgG does not occur immediately - and this is the difference in the reactions of the body during further repeated dates. Our body is unique: it has its own memory archives, where the nature of each of the enemy raids is relentlessly recorded.

So, at the second, third, tenth meeting, the latent phase, during which sleepy flies in the form of immunocompetent cells are disinhibited, lasts several times less: instead of 3-5 days, only a few hours. In addition, there is no switching: the synthesis of immunoglobulins of various classes immediately begins. The organism, despite the unexpectedness of the invasion, is well prepared theoretically and is able to give a much faster rebuff.

From the point of view of the correct staging of the disease, it is diagnostically important that, despite the much later appearance, IgG has a fairly long half-life, which averages 23 days, compared with 2-3 for IgM.

• IgA - can be presented both in serum (up to 10%) and in secretory forms. The latter, by the way, is the leader and provides antimicrobial local immunity in relation to the mucous membranes of the gastrointestinal tract, bronchi, and urinary tract.

Despite the fact that they are not able to pass through the placenta, these immunoglobulins are transferred to the newborn along with mother's milk - another important nuance towards the undeniable benefits of breastfeeding.

Interestingly, some pathogens that invade, as a rule, the mucous membranes of various organs, have specific protection factors against the human body's policemen: protease enzymes that can cleave chemical bonds in the protein molecules of antibodies.

The secretory form of immunoglobulin A is able to specifically recognize and bind to certain areas of antigens - epitopes - in the structures of bacteria, viruses and even toxins.

• IgD is a poorly understood class of antibodies with very low levels in the blood. Their role in the functioning of the immune system is more than unclear.

  It is assumed that they are involved in autoimmune reactions, and also act as receptors for B-lymphocytes.

   

• IgE - their concentration in serum does not exceed 0.004% of the total amount of antibodies. However, such a small content does not prevent them from performing one of the most important tasks: participation in allergic reactions. The latter occur when allergens appear in the serum - foreign substances, which cause the development of hypersensitivity on the part of the body. In this case, their peculiar “binding” of IgE occurs, fixed on mast cells - representatives of the components of the connective tissue. Thus, the organism for the first time gets acquainted with a substance unfamiliar to them.

When the allergen hits again, the already aware immune system immediately activates: the inflammatory mediators deposited in the granules of mast cells (in particular, histamine) are released, which contributes to further tissue damage.

Allergy and pseudo-allergy

For a correct and clear understanding of the problem with which the client contacts you, it is necessary to accurately distinguish between these fundamentally different terms:

• Pseudo-allergy is a pathological process that, according to the manifestation of clinical manifestations and symptoms, is similar or even identical to those that occur with allergies. However, there is no immunological stage in the mechanism of its development - that is, there is no preliminary binding of IgE allergens, but a direct release of inflammatory mediators - in particular, histamine - is immediately observed.

Antibody rates

Reference values ​​for total IgE (mU/l) according to Martins T. et al. (2014)

Immunodeficiencies: types and causes

Both primary and secondary antibody deficiencies can be associated with:

• infections;

• damage to various organs and tissues;

• increased risk of morbidity and mortality.

It is assumed that the insufficiency of immunoglobulins, which is not genetically determined, is usually observed with:

1. A significant loss of protein (after all, antibodies are of a peptide nature), which accompanies various kinds of kidney disease, when large protein molecules that normally do not pass through the narrow cells of the renal filter and remain in the blood end up in the primary urine. In particular, this is typical for nephrotic syndrome.

   In addition, protein loss can also occur through the gastrointestinal tract - this is especially characteristic of celiac disease and intestinal lymphangiectasia caused by obstruction of the lymphatic vessels located in the interstitium, which, in turn, contributes to the outflow of lymph along with immunoglobulins and lymphocytes into intestinal lumen.

    

2. Malignant tumors.

3. Organ and tissue transplants.

4. After the use of certain drugs - for example, the use of corticosteroids (both long-term and short-term).

Depending on which part of the immune system has suffered, all immunodeficiencies can be divided into three large groups:

1. Humoral - associated with a violation of the formation and / or differentiation of B-lymphocytes - future antibody producers.

   Here, in the context of this pathology, I would like to mention once again the inextricably linked reactions of cellular and humoral immunity: after all, in fact, if T-helpers do not shout louder than any police siren to B-lymphocytes: “alarm, alarm!” the production of immunoglobulins will remain closed - work will not begin, the conveyor belts will still be motionless. It usually accompanies two pathological processes

   • the presence of defects in those signaling molecules, with the help of which T-helpers try to reach B-lymphocytes or disturbances in the receptors that perceive them.

   • A decrease in the total number of T-helpers and / or their inability to activate B-lymphocytes.

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   In general, speaking purely about antibody deficiency, it is important to understand the difference between selective and general deficiency: the first refers to a purely one class of immunoglobulins, the formation of which is significantly reduced (most often it is IgA), while the synthesis of others is not impaired or vice versa is compensatory increased. The second one speaks of the pathology of the humoral link of immunity, as such: it is either a complete absence of immunoglobulin production (for example, with the inability of B-lymphocytes to pass into their final mature forms - plasma cells), or a significant decrease.

    

2. Cellular - associated with a violation of the formation or functioning of T-lymphocytes:

   • DiGeorge syndrome is a fairly rare congenital disease that is not inherited and is characterized by a violation of the formation of the thymus gland. The absence of the thymus leads to the fact that T-lymphocytes (not for nothing that they are called thymus-dependent) are not formed - this, in turn, affects the inferiority of the humoral response, which invariably requires the participation of T-helpers.

   • Alymphocytosis is an autosomal recessive disease associated with certain mutations that result in the inability of immature T cells to differentiate into various subpopulations: in particular, T-helpers and T-killers.

    

3. Mixed - both links of immunity are violated: both cellular and humoral. They have the most severe course.

Causes and symptoms of IgA deficiency

This is the most common and widespread (for example, the frequency of the disease in the Arabian Peninsula is only 1:143) pathology of the immune system, genetically determined.

Clear age limits are associated with the immaturity of the immune system in children - in them, a decrease in antibody titers may not be a consequence of congenital immunodeficiencies, but characterize the so-called transient (that is, due to adaptation to a new, extrauterine, life) conditions.

It is believed that this pathology develops when the final stage of maturation of those B-lymphocytes that are “programmed” for the formation of this class of antibodies is disrupted, and, in turn, leads to a compensatory increase in the content of IgG and IgM.

These patients have a more frequent course of allergic diseases, including:

• bronchial asthma;

• hay fever;

• urticaria;

• food allergies.

Scientists and doctors associate this phenomenon with the regular penetration of various foreign allergen agents into the wall of the gastrointestinal tract - into its mucous and submucosal layers, which occurs much more easily and more actively in conditions of such primary immune deficiency.

In addition, studies have documented an increase in the incidence of autoimmune diseases (compared to healthy controls) - and it is noteworthy that female gender was one of the predisposing factors. The most common pathologies were:

• systemic lupus erythematosus;

• rheumatoid arthritis;

• thyroiditis;

• celiac disease

In the context of the treatment of celiac disease, previously described in our blog, we remind you of the need to determine the initial, that is, the general level of IgA before the direct diagnosis of the antibody titer (or rather, autoantibodies - immunoglobulins against their own structures) of this class to endomysium and tissue transglutaminase.

Causes of low immunoglobulin class E

Immunoglobulin E, as previously mentioned, is involved in allergic reactions. However, its second function is no less significant: antibodies of this class provide protection against parasitic infections.

Interesting are the results of a recent study on the relationship between this pathology and infection with Helecobacter, associated primarily with the development of gastritis and its further more serious complications. However, unfortunately, the already proven fact that this type of bacterium, penetrating the gastric mucosa, causes powerful, both local and systemic, production of antibodies and the implementation of protective reactions from cellular immunity, is not so often paid attention.

This pathogen binds to mast cells, causing them to produce multidirectional pro-inflammatory signaling molecules - cytokines. This is partly facilitated by IgE, continuously activating the previously mentioned connective tissue cells.

A low concentration of IgE can be a consequence of both congenital pathologies caused by a gene or chromosomal mutation (ataxia-telangiectasia, Bruton's hypogammaglobulinemia), and accompany acquired diseases:

• chronic fatigue syndrome;

• autoimmune diseases;

• arthralgia.

Deficiency of class G immunoglobulins

Common variable immunodeficiency (CVID) is a primary, in other words, genetically determined, insufficiency of the immune system, which is characterized by a violation of the humoral link and is manifested by hypogammaglobulinemia.

Clinical manifestations in these patients usually include:

1. Development of autoimmune diseases:

   • vitiligo;

   • cytopenias;

   • arthritis.

    

2. Interstitial lung disease.

3. Enteropathy.

4. Lymphoid hyperplasia.

5. Splenomegaly.

Treatment and prevention of immunoglobulin deficiency

With a complete deficiency of immunoglobulins due to certain congenital mutations that occur in the genes responsible for the regulation of this process, the artificial introduction of donor antibodies does not achieve the desired result, but only aggravates the course of the disease - an allergic reaction occurs.

Think about immunological tolerance - the inability of the immune system to produce antibodies against its own antigens (with the exception of the barrier organs, of course). This is a kind of indulgence on her part, the seeds of which are laid during embryonic development - she collides with various molecules and, in the end, develops a clear rule: “these are ours”, and “these are strangers”.

But with the initial absence of antibodies in the body - say, class A - immunocompetent cells are deprived of this opportunity: they have never met them before, in their complexly programmed database centers there is no mention of this substance as their own, which means they start to the most logical solution of the problem in this situation: the destruction of aliens.

Yes, it sounds paradoxical: immunoglobulins against antibodies - but this is not oil and not a play on words, but a real process that occurs for very understandable reasons and mechanisms, on which, by the way, some methods of serological diagnosis of certain diseases are based.

In general, selective immunodeficiency does not always require intervention from doctors - especially if it is asymptomatic. With more severe and, as a rule, pathologies of the immune system detected in the first years of life, either a thymus transplant is performed, or injections of immunoglobulins and antibiotics are prescribed as a preventive measure for bacterial diseases.