Hypergammaglobulinemia is a condition that is characterized by the increased levels of a certain immunoglobulin in the blood serum. The name of the disorder refers to an excess of proteins after serum protein electrophoresis (found in the gammaglobulin region).

Most hypergammaglobulinemias are caused by an excess of immunoglobulin M (IgM), because this is the default immunoglobulin type prior to class switching. Some types of hypergammaglobulinemia are actually caused by a deficiency in the other major types of immunoglobulins, which are IgA, IgE and IgG.

There are 5 types of hypergammaglobulinemias associated with hyper IgM.

MeSH considers hyper IgM syndrome to be a form of dysgammaglobulinemia, not a form of hypergammaglobulinemia .

Hypergammaglobulinemia is a medical condition with elevated levels of gamma globulin.

It is a type of immunoproliferative disorder.

Affects males 50% of the time if mother is a carrier for the gene. Children are fine until 6–9 months of age. Present with recurrent infections with Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, hepatitis virus, and enterovirus CNS infections. Examination shows lymphoid hypoplasia (tonsils and adenoids, no splenomegaly or lymphadenopathy). There is significant decrease in all immunoglobulins.

Hypogammaglobulinemia is a type of primary immunodeficiency disease in which not enough gamma globulins exist in the blood (thus "" + "gamma" + "globulin" + ""). This entails that not enough antibodies exist, which impairs the immune system. Hypogammaglobulinemia is a characteristic of common variable immunodeficiency.

causes:

nephrotic syndrome

Dysgammaglobulinemia is a type of immune disorder characterized by a reduction in some types of gamma globulins, resulting in heightened susceptibility to some infectious diseases where primary immunity is antibody based.

It is distinguished from hypogammaglobulinemia, which is a reduction in "all" types of gamma globulins.

Hyper IgM syndrome can be considered a form of dysgammaglobulinemia, because it results from a failure of transformation from IgM production to production of other antibodies, and so the condition can be interpreted as a reduction of the other types.

X-linked agammaglobulinemia (XLA) is a rare genetic disorder discovered in 1952 that affects the body's ability to fight infection. As the form of agammaglobulinemia that is X-linked, it is much more common in males. In people with XLA, the white blood cell formation process does not generate mature B cells, which manifests as a complete or near-complete lack of proteins called gamma globulins, including antibodies, in their bloodstream. B cells are part of the immune system and normally manufacture antibodies (also called immunoglobulins), which defend the body from infections by sustaining a humoral immunity response. Patients with untreated XLA are prone to develop serious and even fatal infections. A mutation occurs at the Bruton's tyrosine kinase (Btk) gene that leads to a severe block in B cell development (at the pre-B cell to immature B cell stage) and a reduced immunoglobulin production in the serum. Btk is particularly responsible for mediating B cell development and maturation through a signaling effect on the B cell receptor BCR. Patients typically present in early childhood with recurrent infections, in particular with extracellular, encapsulated bacteria. XLA is deemed to have a relatively low incidence of disease, with an occurrence rate of approximately 1 in 200,000 live births and a frequency of about 1 in 100,000 male newborns. It has no ethnic predisposition. XLA is treated by infusion of human antibody. Treatment with pooled gamma globulin cannot restore a functional population of B cells, but it is sufficient to reduce the severity and number of infections due to the passive immunity granted by the exogenous antibodies.

XLA is caused by a mutation on the X chromosome of a single gene identified in 1993 which produces an enzyme known as Bruton's tyrosine kinase, or Btk. XLA was first characterized by Dr. Ogden Bruton in a ground-breaking research paper published in 1952 describing a boy unable to develop immunities to common childhood diseases and infections. It is the first known immune deficiency, and is classified with other inherited (genetic) defects of the immune system, known as primary immunodeficiency disorders.

Persons afflicted with X-SCID often have infections very early in life, before three months of age. This occurs due to the decreased amount of immunoglobulin G (IgG) levels in the infant during the three-month stage. This is followed by viral infections such as pneumonitis, an inflammation of the lung which produces common symptoms such as cough, fever, chills, and shortness of breath. A telltale sign of X-SCID is candidiasis, a type of fungal infection caused by "Candida albicans". Candidiasis involves moist areas of the body such as skin, the mouth, respiratory tract, and vagina; symptoms of oral candidiasis include difficulty in swallowing, pain on swallowing and oral lesions. Recurrent eczema-like rashes are also a common symptom. Other common infections experienced by individuals with X-SCID include diarrhea, sepsis, and otitis media. Some other common symptoms that are experienced by X-SCID patients include failure to thrive, gut problems, skin problems, and muscle hypotonia.

In some patients symptoms may not appear for the first six months after birth. This is likely due to passive immunity received from the mother in order to protect the baby from infections until the newborn is able to make its own antibodies. As a result, there can be a silent period where the baby displays no symptoms of X-SCID followed by the development of frequent infections.

Gluten-sensitive enteropathy–associated conditions are comorbidities or complications of gluten-related gastrointestinal distress (that is, gluten-sensitive enteropathy or GSE). GSE has key symptoms typically restricted to the bowel and associated tissues; however, there are a wide variety of associated conditions. These include bowel disorders (diarrhoea, constipation, irritable bowel), eosinophilic gastroenteritis and increase with coeliac disease (CD) severity. With some early onset and a large percentage of late onset disease, other disorders appear prior to the celiac diagnosis or allergic-like responses (IgE or IgA, IgG) markedly increased in GSE. Many of these disorders persist on a strict gluten-free diet (GF diet or GFD), and are thus independent of coeliac disease after triggering. For example, autoimmune thyroiditis is a common finding with GSE.

However, GSEs' association with disease is not limited to common autoimmune diseases. Coeliac disease has been found at increased frequency on followup to many autoimmune diseases, some rare. Complex causes of autoimmune diseases often demonstrates only weak association with coeliac disease. The frequency of GSE is typically around 0.3 to 1% and lifelong risk of this form of gluten sensitivity increases in age, possibly as high as 2% for people over 60 years of age. This coincides with the period in life when late-onset autoimmune diseases also rise in frequency.

Genetic studies indicate that coeliac disease genetically links to loci shared by linkage with other autoimmune diseases. These linkages may be coincidental with how symptomatic disease is selected from a largely asymptomatic population.

The signs and symptoms of DOCK8 deficiency are similar to the autosomal dominant form, STAT3 deficiency. However, in DOCK8 deficiency, there is no skeletal or connective tissue involvement, and affected individuals do not have the characteristic facial features of those with autosomal dominant hyper-IgE syndrome. DOCK8 deficient children often have eczema, respiratory and skin staphylococcus infections.

Beyond these, many other recurrent infections have been observed, including recurrent fungal infections and recurrent viral infections (including molluscum contagiosum, herpes simplex, and herpes zoster), recurrent upper respiratory infection (including "Streptococcus pneumoniae", "Haemophilus influenzae", respiratory syncytial virus, and adenovirus), recurrent sinusitis, recurrent otitis media, mastoiditis, pneumonia, bronchitis with bronchiectasis, osteomyelitis, candidiasis, meningitis (caused by cryptococcus or H. influenzae), pericarditis, salmonella enteritis, and giardiasis. Other dermatologic problems include squamous-cell carcinoma/dysplasia (vulvar, anal, and facial). Immune problems are also common, including autoimmune hemolytic anemia, severe allergies (both food and environmental), asthma, and reactive airway disease. The nervous system may also be affected; observed conditions in DOCK8 deficient people include hemiplegia, ischemic stroke, subarachnoid hemorrhage, and facial paralysis. Vascular complications are common, including aortic aneurysm, cerebral aneurysm, vessel occlusion and underperfusion, and leukocytoclastic vasculitis.

Treatment is by parenteral administration of gamma globulins, either monthly intravenously, or, more recently, by weekly self-administered hypodermoclysis. In either case, mild allergic reactions (generalized pruritus, urticaria) are common, and are usually manageable with oral diphenhydramine.

A study of patients with "dermatitis herpetiformis" or coeliac disease revealed significantly more

gluten in the blood than controls. This increases the risk of asthma, anaphylaxis and dermatological conditions.

DOCK8 deficiency, also called DOCK8 immunodeficiency syndrome, is the autosomal recessive form of hyperimmunoglobulin E syndrome, a genetic disorder characterized by elevated immunoglobulin E levels, eosinophilia, and recurrent infections with staphylococcus and viruses. It is caused by a mutation in the "DOCK8" gene.

X-linked severe combined immunodeficiency (X-SCID) is an immunodeficiency disorder in which the body produces very few T cells and NK cells. In the absence of T cell help, B cells become defective. It is an x-linked recessive trait, stemming from a mutated (abnormal) version of the IL2-RG gene located at xq13.1 on the X-chromosome, which is shared between receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21.

WHIM Syndrome (or Warts, Hypogammaglobulinemia, Immunodeficiency, and Myelokathexis syndrome) is a rare congenital immunodeficiency disorder characterized by chronic noncyclic neutropenia.

Factor XII deficiency (also Hageman factor deficiency) is a deficiency in the production of factor XII (FXII), a plasma glycoprotein and clotting factor that participates in the coagulation cascade and activates factor XI. FXII appears to be not essential for blood clotting, as individuals with this condition are usually asymptomatic and form blood clots in vivo. FXII deficiency tends to be identified during presurgical laboratory screening for bleeding disorders.

The condition can be inherited or acquired.

Warm antibody autoimmune hemolytic anemia (WAIHA) is the most common form of autoimmune hemolytic anemia. About half of the cases are of unknown cause, with the other half attributable to a predisposing condition or medications being taken. Contrary to cold autoimmune hemolytic anemia (e.g., cold agglutinin disease and paroxysmal cold hemoglobinuria) which happens in cold temperature (28–31 °C), WAIHA happens at body temperature.

While it is indicated that people with FXII deficiency are generally asymptomatic, studies in women with recurrent miscarriages suggest an association with FXII deficiency.

The condition is of importance in the differential diagnosis to other bleeding disorders, specifically the hemophilias: hemophilia A with a deficiency in factor VIII or antihemophilic globulin, hemophilia B with a deficiency in factor IX (Christmas disease), and hemophilia C with a deficiency in factor XI. Other rare forms of bleeding disorders are also in the differential diagnosis.

There is concern that individuals with FXII deficiency are more prone to thrombophilic disease, however, this is at variance with a long term study from Switzerland.

AIHA may be:

- Idiopathic, that is, without any known cause

- Secondary to another disease, such as an antecedent upper respiratory tract infection, systemic lupus erythematosus or a malignancy, such as chronic lymphocytic leukemia (CLL)

HIES often appears early in life with recurrent staphylococcal and candidal infections, pneumonias, and eczematoid skin.

- Autosomal dominant Hyper-IgE Syndrome caused by STAT3 defects, called Job Syndrome, have characteristic facial, dental, and skeletal abnormalities. Patients with STAT3 HIES may have either delay of or failure in shedding of primary teeth. The characteristic facial features are usually set by age 16. These include facial asymmetry, a prominent forehead, deep-set eyes, a broad nasal bridge, a wide, fleshy nasal tip, and mild prognathism. Additionally, facial skin is rough with prominent pores. Finally, some patients with STAT3 HIES have scoliosis, as well as bones that fracture easily.

- Autosomal recessive

Elevated IgE is the hallmark of HIES. An IgE level greater than 2,000 IU/mL is often considered diagnostic. However, patients younger than 6 months of age may have very low to non-detectable IgE levels. Eosinophilia is also a common finding with greater than 90% of patients having eosinophil elevations greater than two standard deviations above the normal mean. Genetic testing is available for "STAT3" (Job's Syndrome), "DOCK8 (DOCK8 Immunodeficiency or DIDS)", "PGM3" (PGM3 deficiency), "SPINK5" (Netherton Syndrome - NTS), and "TYK2" genetic defects.

Patients exhibit increased susceptibility to bacterial and viral infections, especially from common serotype human papilloma virus, resulting in warts on the hands and feet starting in childhood. Myelokathexis refers to retention (kathexis) of neutrophils in the bone marrow (myelo). In addition, lymphocytes and IgG antibody levels (gammaglobulins) are often deficient.

An example of a tuberculosis (TB) infection that comes under control: "M. tuberculosis" cells are engulfed by macrophages after being identified as foreign, but due to an immuno-escape mechanism peculiar to mycobacteria, TB bacteria are able to block the fusion of their enclosing phagosome with lysosomes which would destroy the bacteria. Thereby TB can continue to replicate within macrophages. After several weeks, the immune system somehow [mechanism as yet unexplained] ramps up and, on stimulation with IFN-gamma, the macrophages become capable of killing "M. tuberculosis" by forming phagolysosomes and nitric oxide radicals. The hyper-activated macrophages secrete TNF-α which recruits multiple monocytes to the site of infection. These cells differentiate into epithelioid cells which wall off the infected cells, but results in significant inflammation and local damage.

Some other clinical examples:

- Temporal arteritis

- Leprosy

- Coeliac disease

- Graft-versus-host disease

- Chronic transplant rejection

Barraquer–Simons syndrome (or acquired partial lipodystrophy, cephalothoracic lipodystrophy, and progressive lipodystrophy)) is a rare form of lipodystrophy,

which usually first affects the head, and then spreads to the thorax.

It is named for Luis Barraquer Roviralta (1855–1928), a Spanish physician, and Arthur Simons (1879–1942), a German physician. Some evidence links it to "LMNB2".

At least one physician associates the symptoms with tuberculosis. Some lethal overwhelming infections are reported, aggravating people who already suffer other conditions such as HIV/AIDS.

Hemolytic disease of the newborn, also known as hemolytic disease of the fetus and newborn, HDN, HDFN, or erythroblastosis fetalis, is an alloimmune condition that develops in a fetus, when the IgG molecules (one of the five main types of antibodies) produced by the mother pass through the placenta. Among these antibodies are some which attack antigens on the red blood cells in the fetal circulation, breaking down and destroying the cells (hemolysis). The fetus can develop reticulocytosis and anemia. This fetal disease ranges from mild to very severe, and fetal death from heart failure (hydrops fetalis) can occur. When the disease is moderate or severe, many erythroblasts (immature red blood cells) are present in the fetal blood, and so these forms of the disease can be called "erythroblastosis fetalis" (or "erythroblastosis foetalis").

HDFN represents a breach of immune privilege for the fetus or some other form of impairment of the immune tolerance of pregnancy. Various types of HDFN are classified by which alloantigen provokes the response. In order of incidence, the types include ABO, anti-RhD, anti-RhE, anti-Rhc, anti-Rhe, anti-RhC, multiantigen combinations, and anti-Kell.