Selective IgA deficiency is the most common primary immunodeficiency ; it is defined as decreased serum level of IgA in the presence of other normal Ig isotypes, T-cell immunity, and natural killer activity. The worldwide incidence of IgA deficiency differs by ethnic background, in Caucasians being much higher than that in Asians, with a prevalence of around 1:3000 in US [2]. IgA is the key Ig in the respiratory and GI tracts, which provide the most intimate interface between the environment and self [3]. The manifestations are variable in IgA deficiency patients: from asymptomatic condition (in up to 90 % of subjects) to recurrent infections of the respiratory (particularly H. influenzae and Streptococcus pneumonia) and GI tracts, autoimmune diseases, allergies, and malignancies. Autoimmune diseases are a frequent finding in IgA deficiency, mainly autoimmune cytopenias, juvenile rheumatoid arthritis, thyroiditis, systemic lupus erythematosus, and celiac disease. IgA deficiency sometimes progress to common variable immunodeficiency (CVID); in fact, the diseases often share a common genetic and familial predisposition (IGAD1) [2]. Other related conditions include anaphylactic transfusion reactions; the patients should be screened for anti-IgA antibodies and treated with low or absent IgA blood products if the need for transfusion arises. GI manifestations are frequent in patients with selective IgA deficiency. Giardia lamblia infections can occur in these patients, causing bloating, cramping, excessive flatus, and watery diarrhea. The infection can be chronic, despite treatment with metronidazole, resulting in malabsorption with steatorrhea and villus flattening [4]. The degree of mucosal damage is related to the duration of the infection. Diagnosis is made by examining the stool for cysts or trophozoites of G. lamblia, or by examination of duodenal aspirates, which can yield more determinate results. The incidence of selective IgA deficiency has been demonstrated to be higher in celiac disease than in the general population, given shared human leukocyte antigen (HLA) haplotypes. Secretory IgA can bind to wheat gluten and gliadin, and the absence of IgA may lead to abnormal processing of these antigens [4]. The symptoms of celiac disease are similar in patients with or without IgA deficiency, the only differentiating feature is that immunohistochemical staining of small-intestinal biopsies reveals an absence of IgA-secreting plasma cells in IgA-deficient patients. Antigliadin IgA, antitissue transglutaminase IgA, and antiendomysial IgA antibodies cannot be used as screening tests for this population, tissue transglutaminase IgG may be a better screening test [4]. Celiac disease associated with IgA deficiency is responsive to gluten withdrawal, failure to respond to a gluten-free diet should lead one to consider CVID.

Nodular lymphoid hyperplasia also is documented in IgA deficiency. Multiple nodules are found in the lamina propria, superficial submucosa of the small intestine, or both, and occasionally can occur in the stomach, large intestine, or rectum. The lesions can be associated with mucosal flattening, causing malabsorption and even obstruction when large. Diagnosis is made by small-bowel endoscopy sometime with the help of contrast barium or MRI studies. Large amounts of IgM-bearing cells can be found in the immunohistochemical staining, possibly as compensation for the absent IgA. These patients may benefit from oral steroid therapy [4]. Rarely, patients with IgA deficiency can develop pernicious anemia, inflammatory bowel disease, lymphomas (usually B cell origin), and gastric carcinomas. The diagnosis is based on the measurement of IgA concentration in serum; normal levels of IgA are dependent by age, ethnicity, gender, and body habits. The international consensus for diagnosing a selective IgA deficiency is a serum level of below 0.07 g/l in individuals over 4 years of age accompanied by normal levels of IgG and IgM [2]. The threshold of 4 years of age is used to avoid premature diagnosis of IgA deficiency which may be transient in younger children due to delayed ontogeny of IgA system after birth [3]. In IgA deficiency, the mainstay of the therapeutic approach is the treatment of associated diseases. If the patient experiences recurrent infections, daily prophylactic antibiotics on a continuous or seasonal intermittent basis may be beneficial [3]. IL-21 or the combination of CD40 L/anti-CD40, IL-4, and IL-10 are potential targets for new therapeutic modalities [2, 5].

XLA results from a maturation arrest of pre-B cells with subsequent B cell generation failure, no plasma cell in lymphoid tissues, virtual absence of all classes of Ig, small tonsils, and lymphonodes. They are typically male infants or young children. The incidence is approximately 1 in 100,000 live births. Female carriers can be detected, and prenatal diagnosis of affected or unaffected male fetuses can be accomplished. XLA results from a defect of Bruton’s tyrosine kinase (BKT), a member of Tec family protein. It is an intracellular tyrosine-kinase protein, expressed in most of hematopoietic cells: It presents high levels in all B-cells line, but it is not expressed in T cell precursors and natural killer (NK) cells. BKT gene is located on the proximal part of the long arm of the X chromosome. There are about 554 different mutations of BKT gene, but it seems that there is no correlation between mutation location and clinical phenotype. The abnormal BKT induce a maturational arrest of B lymphocytes at the pre-B cell stage and secondary inability to produce antibody after antigen stimulation. A normal number of pre-B cells are found in the bone marrow, but no mature B cells. Peripheral CD19, CD20, and CD23 B cells are usually less than 0.1 %. IgG, IgA, and IgM levels are virtually absent. There is no production of isohemagglutinins or antibody after vaccinations. There are, also, five different autosomal recessive defects that cause agammaglobulinemia [6]. These include: (1) µ (IgM heavy chain deficiency), (2) Ig-α(CD79a9 deficiency, (3) B cell linker adaptor protein (BLNK) deficiency, (4) surrogate light chain (lambda 5 or CD179b) deficiency, (5) leucine-rich repeat containing 8 (LRRC8). All these forms present similar immunological and clinical phenotypes to XLA but are less common. The majority of males with XLA are asymptomatic during the first 4–6 months of life thanks to mother’s transmitted antibodies [7]. Then they present severe and repeated infections caused, mainly, by extracellular pyogenic and encapsulated organisms, often gram-positive (such as S. pneumonia, Staphylococcus Aureus, Neisseria, Haemophilus or Mycoplasma). The infections may interest respiratory, GI, and genitourinary tracts. Systemic infections (septicemia or meningitis) are less common but frequent, as well as osteomyelitis, septic arthritis, cellulitis or skin abscesses. In such cases, we can observe chronic fungal infection or Pnemocystis jirovecii pneumonia. Viral infections are, usually, self-limiting except hepatitis or enteroviruses despite a good T-cell response. GI manifestations are less common in XLA compared to other antibody-deficiency syndromes and to CVID. The most frequent GI symptom is chronic diarrhea that is often accompanied by secondary malabsorptive syndrome associated with a protein-losing enteropathy [8]. The main pathogens involved in these infectious diarrheas are G. lamblia, Salmonella, Campylobacter, and Cryptosporidium; enteroviral infections (such as Coxsackievirus and Echovirus) are also common and can lead to severe neurologic defects. Sometimes chronic diarrhea is related to small bowel bacterial overgrowth. It is important that GI infection treatments are based on adapted culture methods and adequate prolonged therapy. Cases of malabsorption and bacteremia due to infection of Helicobacter pylori and Campylobacter jejuni resistant to many antibiotics have been described [9]. Some patients with XLA present small-bowel strictures and transmural intestinal fissures similar to Crohn’s disease, without granulomas or plasma cells. XLA patients generally do not develop nodular lymphoid hyperplasia. The disease, occasionally, manifests with different clinical spectrums such as autoimmune diseases or cancer (gastric adenocarcinoma and colorectal cancer). In particular, chronic atrophic gastritis with pernicious anemia is also a common finding that predisposes to gastric adenocarcinoma. In spite of these infections, patients with XLA may not have failure to thrive unless they develop bronchiectasis. The most common cause of death was chronic enteroviral infection [10]. Diagnosis is based on clinical features and typical laboratory results (profound reduction in all classes of Ig and depressed or absent humoral response to specific antigens, peripheral CD19+ B cell usually < 0.1 % with preserved T cell number and function) and, it could be confirmed by genetic mutation analysis [11]. An early diagnosis of XLA with immediate initiation of therapy is crucial for ensuring good outcomes for the affected patients. Delayed diagnosis could lead to long-lasting sequelae such as bronchiectasis, hearing loss, or liver cirrhosis due to chronic hepatitis. XLA treatment consists of replacement IgG therapy (intravenous gammaglobulin, IVGG); either intravenous or subcutaneous. Early IVGG replacement therapy decreases the rates of admission and morbidity for chronic complications, such as bronchiectasis and chronic lung disease, and prevents fatal complications like meningoencephalitis. Appropriate IVGG should be started at 6–8 weeks of age because around 25 % of the XLA patients show clinical symptoms before 4 months of age. Antibiotics treatment for documented or suspected infections is necessary because commercial preparations of IgG could not have adequate titers against uncommon organisms.

Hyper-IgM syndromes are a group of rare inherited immunodeficiencies characterized by impairment of Ig isotype switching resulting from defects in the CD40 ligand/CD40 signaling pathway. They are characterized by high levels of IgM associated with low or absent levels of IgG, IgA, and IgE [12]. This “class switch” is critical to host resistance to bacterial infections. There are several mutations that caused hyper-IgM syndrome:

Distinctive clinical features for these patients allow presumptive recognition of mutation, this is important to choose the best therapy. The range of clinical findings varies, even within the same family. Over 50 % of males with HIGM1 develop symptoms by the age of 1 year, and more than 90 % are symptomatic by the age of 4 years. The clinical presentation of X-linked hyper-IgM is similar to XLA, with recurrent pyogenic infections such as otitis, sinusitis, pneumonia, or tonsillitis that start in the first 2 years of life. These patients are also susceptible to a variety of intracellular pathogens as mycobacterial species, fungi, and viruses; in about 40 % of cases, we found pneumonia by Pneumocystis jirovecii. Significant neurologic complications are seen in 10–15 % of males with HIGM1. However, in at least one half of affected individuals a specific infectious agent cannot be isolated. GI symptoms include mostly chronic diarrhea and liver involvement. The main pathogens that caused diarrhea are Cryptosporidium parvum (the most common), G. lamblia, Salmonella, or Entameba histolytica. Chronic diarrhea is a frequent complication of HIGM1, occurring in approximately one third of affected males. Recurrent or protracted diarrhea may result from infection with C. parvum or other microorganisms; however, in at least 50 % of males with recurrent or protracted diarrhea, no infectious agent can be detected. It can cause failure to thrive and weight loss. Neutropenia often causes oral or rectal ulcers and gingivitis or mucosal abscess. Liver disease, a serious complication of HIGM1, historically was observed in more than 80 % of affected males by age 20 years. Hepatic involvement presents: cholangiopathy with Cryptosporidium in the biliary tree, B and C hepatitis and cytomegalovirus (CMV) infections with a possible evolution in cirrhosis or hepatocellular carcinoma . It can result in disturbed liver increased gamma-glutamyltransferase levels; this alteration can predict a possible development of sclerosing cholangitis with a risk of cholangiocarcinoma. Tumors of the GI tract (carcinoid of the pancreas, glucagonoma) are common life-threatening complications in adolescents and young adults with HIGM1 [13]. Affected males also have an increased risk for lymphoma, particularly Hodgkin’s disease associated with Epstein–Barr virus infection. Autosomal recessive forms have usually a later onset and present often autoimmune disorders (such as diabetes mellitus, autoimmune hepatitis, autoimmune thrombocytopenia, and Crohn’s disease). Neutropenia is less common. The reported median survival of males with HIGM1 who do not undergo successful allogeneic bone marrow transplantation is less than 25 years. P. jirovecii pneumonia in infancy, liver disease , and carcinomas of the liver and GI tract in adolescence or young adulthood are the major causes of death [14]. Laboratory evaluation is fundamental: These patients have low or absent levels of IgG, IgE, and IgA associated to normal or high level of IgM (very high levels of IgM are typical of autosomal recessive form) and IgD. B and T lymphocyte number are usually normal. The diagnosis of HIGM1 is based on a combination of clinical findings, family history, absent or decreased expression of the CD40 ligand (CD40L) protein on flow cytometry following in vitro stimulation of white cells, and molecular genetic testing of CD40LG (previously known as TNFSF5 or CD154). The only curative treatment currently available is allogeneic hematopoietic cell transplantation, ideally performed prior to the onset of life-threatening complications and organ damage. Other effective therapies are monthly replacement of Ig and antibiotics for specific infectious complications. To reduce the risk of Cryptosporidium infection is recommended that patients boil or filter water. In patients with neutropenia is possible use granulocyte colony-stimulating factor (G-CSF).