Distinction between primary versus secondary immunodeficiencies are based on, respectively, whether the cause originates in the immune system itself or is, in turn, due to insufficiency of a supporting component of it or an external decreasing factor of it.

In reality, immunodeficiency often affects multiple components, with notable examples including severe combined immunodeficiency (which is primary) and acquired immune deficiency syndrome (which is secondary).

Signs/symptoms of humoral immune deficiency depend on the cause, but generally include signs of infection such as:

- Sinusitis

- Sepsis

- Skin infection

- Pneumonia

An opportunistic infection is an infection caused by pathogens (bacteria, viruses, fungi, or protozoa) that take advantage of an opportunity not normally available, such as a host with a weakened immune system, an altered microbiota (such as a disrupted gut flora), or breached integumentary barriers. Many of these pathogens do not cause disease in a healthy host that has a normal immune system. However, a compromised immune system, a penetrating injury, or a lack of competition from normal commensals presents an opportunity for the pathogen to infect.

The symptoms of CVID vary between people affected. Its main features are hypogammaglobulinemia and recurrent infections. Hypogammaglobulinemia manifests as a significant decrease in the levels of IgG antibodies, usually alongside IgA antibodies; IgM antibody levels are also decreased in about half of people. Infections are a direct result of the low antibody levels in the circulation, which do not adequately protect them against pathogens. The microorganisms that most frequently cause infections in CVID are bacteria Haemophilus influenzae, Streptococcus pneumoniae and Staphylococcus aureus. Pathogens less often isolated from people include Neisseria meningitidis, Pseudomonas aeruginosa and Giardia lamblia. Infections mostly affect the respiratory tract (nose, sinuses, bronchi, lungs) and the ears; they can also occur at other sites, such as the eyes, skin and gastrointestinal tract. These infections respond to antibiotics but can recur upon discontinuation of antibiotics. Bronchiectasis can develop when severe, recurrent pulmonary infections are left untreated.

In addition to infections, people with CVID can develop complications. These include:

- autoimmune manifestations, e.g. pernicious anemia, autoimmune haemolytic anemia (AHA), idiopathic thrombocytopenic purpura (ITP), psoriasis, vitiligo, rheumatoid arthritis, primary hypothyroidism, atrophic gastritis. Autoimmunity is the main type of complication in people with CVID, appearing in some form in up to 50% of individuals;

- malignancies, particularly Non-Hodgkin's lymphoma and gastric carcinoma;

- enteropathy, which manifests with a blunting of intestinal villi and inflammation, and is usually accompanied by symptoms such as abdominal cramps, diarrhea, constipation and, in some cases, malabsorption and weight loss. Symptoms of CVID enteropathy are similar to those of celiac disease, but don't respond to a gluten-free diet. Infectious causes must be excluded before a diagnosis of enteropathy can be made, as people with CVID are more susceptible to intestinal infections, e.g. by Giardia lamblia;

- lymphocytic infiltration of tissues, which can cause enlargement of lymph nodes (lymphadenopathy), of the spleen (splenomegaly) and of the liver (hepatomegaly), as well as the formation of granulomas. In the lung this is known as Granulomatous–lymphocytic interstitial lung disease.

Anxiety and depression can occur as a result of dealing with the other symptoms.

People generally complain of severe fatigue.

Immunodeficiency or immunosuppression can be caused by:

- Malnutrition

- Fatigue

- Recurrent infections

- Immunosuppressing agents for organ transplant recipients

- Advanced HIV infection

- Chemotherapy for cancer

- Genetic predisposition

- Skin damage

- Antibiotic treatment leading to disruption of the physiological microbiome, thus allowing some microorganisms to outcompete others and become pathogenic (e.g. disruption of intestinal flora may lead to "Clostridium difficile" infection

- Medical procedures

- Pregnancy

- Ageing

- Leukopenia (i.e. neutropenia and lymphocytopenia)

The lack of or the disruption of normal vaginal flora allows the proliferation of opportunistic microorganisms and will cause the opportunistic infection - bacterial vaginosis.

Cause of this deficiency is divided into "primary" and "secondary":

- Primary the International Union of Immunological Societies classifies primary immune deficiencies of the humoral system as follows:

- Secondary secondary (or acquired) forms of humoral immune deficiency are mainly due to hematopoietic malignancies and infections that disrupt the immune system:

AIDS-related complex, or ARC, was introduced after discovery of the HIV (Human Immunodeficiency Virus) when the medical community became aware of the inherent difficulties associated with treating patients suffering from an advanced case of HIV which gave rise to the term Acquired Immune Deficiency Syndrome (AIDS). The necessity for doctors to quickly and accurately understand the special needs of unknown patients suffering from AIDS in an emergency room situation was addressed with the creation of the term ARC.

ARC is "A prodromal phase of infection with the human immunodeficiency virus (HIV). Laboratory criteria separating AIDS-related complex ( ARC) from AIDS include elevated or hyperactive B-cell humoral immune responses, compared to depressed or normal antibody reactivity in AIDS; follicular or mixed hyperplasia in ARC lymph nodes, leading to lymphocyte degeneration and depletion more typical of AIDS; evolving succession of histopathological lesions such as localization of Kaposi's sarcoma, signaling the transition to the full-blown AIDS."

Clinical use of this term was widely discontinued by the year 2000 in the United States after having been replaced by modern laboratory criteria.

Common variable immunodeficiency (CVID) is an immune disorder characterized by recurrent infections and low antibody levels, specifically in immunoglobulin (Ig) types IgG, IgM and IgA. Generally symptoms include high susceptibility to foreign invaders, chronic lung disease, and inflammation and infection of the gastrointestinal tract. However, symptoms vary greatly between people. CVID is a lifelong disease.

The cause of CVID is poorly understood. Deletions in genes that encode cell surface proteins and cytokine receptors, such as CD19, CD20, CD21, and CD80, is a likely cause. A deletion is a mutation in which part of the chromosome is lost during DNA replication which may include several genes, or as few as a single base pair. Additionally, the disease is defined by T cell defects, namely reduced proliferative capacity. The disease is hard to diagnose, taking on average 6–7 years after onset.

Treatment options are limited, and usually include lifelong immunoglobulin replacement therapy. This therapy is thought to help reduce bacterial infections. This treatment alone is not wholly effective, and many people still experience other symptoms like lung disease and noninfectious inflammatory symptoms.

CVID was first diagnosed over 60 years ago, and since has emerged as the predominant class of primary antibody deficiencies. CVID is formally diagnosed by levels of IgG and IgA more than two standard deviations from the norm, and no other cause for hypogammaglobulinemia, an abnormally low level of immunoglobulins in the blood. It is thought to affect between 1 in 25,000 to 1 in 50,000 people worldwide.

Combined immunodeficiencies (or combined immunity deficiency) are immunodeficiency disorders that involve multiple components of the immune system, including both humoral immunity and cell-mediated immunity.

This category includes conditions such as bare lymphocyte syndrome, as well as severe combined immunodeficiency.

ICD-9 divides immune deficiencies into three categories: humoral (279.0), cell-mediated (279.1), and combined (279.2). However, ICD-10 does not include a category for cell-mediated immune dysfunction (antibody is D80, and combined is D81), thus grouping T-cell mediated conditions with combined conditions.

An autoimmune disease is a condition arising from an abnormal immune response to a normal body part. There are at least 80 types of autoimmune diseases. Nearly any body part can be involved. Common symptoms include low grade fever and feeling tired. Often symptoms come and go.

HIV-SGD may be the presenting sign of HIV infection. There may also be xerophthalmia (dry eyes) and arthralgia (joint pain), similar to Sjögren syndrome.

A minority of patients are diagnosed with thymoma prior to manifestation of the immunodeficient state. Spindle-cell histology is present in most cases.

Because patients with GS have deficient humoral and cellular immunity, they are susceptible to a wide range of infections. Most commonly these patients suffer from respiratory tract infections. Chronic diarrhea is often related to villous atrophy rather than infection (Kelesidis, 2010).

Often autoimmune disease is associated with GS - most commonly pure red cell aplasia and myasthenia gravis. While the patients may experience hypogammaglobulinemia, a large percentage will have autoantibodies present in their serum (Kelesidis, 2010). It is theorized that the presence of thymoma may inhibit the thymus’s normal role in production of self-tolerant T lymphocytes. These T-lymphocytes may then attack the B cell precursors in the marrow, preventing maturation and ultimately resulting in hypogammaglobulinemia (Arnold, 2015).

The precise symptoms of a primary immunodeficiency depend on the type of defect. Generally, the symptoms and signs that lead to the diagnosis of an immunodeficiency include recurrent or persistent infections or developmental delay as a result of infection. Particular organ problems (e.g. diseases involving the skin, heart, facial development and skeletal system) may be present in certain conditions. Others predispose to autoimmune disease, where the immune system attacks the body's own tissues, or tumours (sometimes specific forms of cancer, such as lymphoma). The nature of the infections, as well as the additional features, may provide clues as to the exact nature of the immune defect.

There are no formal diagnostic criteria (Kelleher, 2003) and many informal definitions exist. Most commonly thymoma is present with mixed humoral and cellular immune deficiency. T and B cells are both depleted so patients suffer from both encapsulated organisms as well as opportunistic infections (Miyakis, 2005). Some have defined GS as a subset of common variable immunodeficiency (CVID). Unlike CVID, there are reduced B cells in the periphery in GS (Kelesidis, 2010).

More generally it can be defined as an adult-onset primary immunodeficiency associated with thymoma, hypogammaglobulinemia, diminished B and T cells, and inverted CD4/CD8+ ratio(Kelesidis, 2010).

XMEN patients have splenomegaly, chronic Epstein Barr Virus (EBV) infection, and are developmentally normal. They have an increased susceptibility for developing EBV+ lymphoma. Additionally, XMEN patients have excessive infections consistent with the underlying immunodeficiency. These infections included recurrent otitis media, sinusitis, viral pneumonia, diarrhea, upper respiratory infections, epiglottitis, and pertussis. Although autoimmune symptoms do not feature prominently in XMEN autoimmune cytopenias were observed in two unrelated patients.

In the figure to the left, major features are present in all XMEN patients, while minor features are found only in some.

HIV-SGD is more prevalent in HIV positive children than HIV positive adults, at about 19% and 1% respectively. Unlike other oral manifestations of HIV/AIDS such as Kaposi sarcoma, oral hairy leukoplakia and oral candidiasis, which decreased following the introduction of highly active antiretroviral therapy (HAART), HIV-SGD has increased.

The International Union of Immunological Societies recognizes nine classes of primary immunodeficiencies, totaling over 120 conditions. A 2014 update of the classification guide added a 9th category and added 30 new gene defects from the prior 2009 version.

An immune disorder is a dysfunction of the immune system. These disorders can be characterized in several different ways:

- By the component(s) of the immune system affected

- By whether the immune system is overactive or underactive

- By whether the condition is congenital or acquired

According to the International Union of Immunological Societies, more than 150 primary immunodeficiency diseases (PIDs) have been characterized. However, the number of acquired immunodeficiencies exceeds the number of PIDs.

It has been suggested that most people have at least one primary immunodeficiency. Due to redundancies in the immune system, though, many of these are never detected.

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.

Severe combined immunodeficiency, SCID, also known as alymphocytosis, Glanzmann–Riniker syndrome, severe mixed immunodeficiency syndrome, and thymic alymphoplasia, is a rare genetic disorder characterized by the disturbed development of functional T cells and B cells caused by numerous genetic mutations that result in heterogeneous clinical presentations. SCID involves defective antibody response due to either direct involvement with B lymphocytes or through improper B lymphocyte activation due to non-functional T-helper cells. Consequently, both "arms" (B cells and T cells) of the adaptive immune system are impaired due to a defect in one of several possible genes. SCID is the most severe form of primary immunodeficiencies, and there are now at least nine different known genes in which mutations lead to a form of SCID. It is also known as the bubble boy disease and bubble baby disease because its victims are extremely vulnerable to infectious diseases and some of them, such as David Vetter, have become famous for living in a sterile environment. SCID is the result of an immune system so highly compromised that it is considered almost absent.

SCID patients are usually affected by severe bacterial, viral, or fungal infections early in life and often present with interstitial lung disease, chronic diarrhoea, and failure to thrive. Ear infections, recurrent "Pneumocystis jirovecii" (previously carinii) pneumonia, and profuse oral candidiasis commonly occur. These babies, if untreated, usually die within one year due to severe, recurrent infections unless they have undergone successful hematopoietic stem cell transplantation.

About half of US states are performing screening for SCID in newborns using real-time quantitative PCR to measure the concentration of T-cell receptor excision circles. Wisconsin and Massachusetts (as of February 1, 2009) screen newborns for SCID. Michigan began screening for SCID in October 2011. Some SCID can be detected by sequencing fetal DNA if a known history of the disease exists. Otherwise, SCID is not diagnosed until about six months of age, usually indicated by recurrent infections. The delay in detection is because newborns carry their mother's antibodies for the first few weeks of life and SCID babies look normal.

85–90% of IgA-deficient individuals are asymptomatic, although the reason for lack of symptoms is relatively unknown and continues to be a topic of interest and controversy. Some patients with IgA deficiency have a tendency to develop recurrent sinopulmonary infections, gastrointestinal infections and disorders, allergies, autoimmune conditions, and malignancies. These infections are generally mild and would not usually lead to an in-depth workup except when unusually frequent.

They may present with severe reactions including anaphylaxis to blood transfusions or intravenous immunoglobulin due to the presence of IgA in these blood products. Patients have an increased susceptibility to pneumonia and recurrent episodes of other respiratory infections and a higher risk of developing autoimmune diseases in middle age.

IgA deficiency and common variable immunodeficiency (CVID) feature similar B cell differentiation arrests, it does not present the same lymphocyte subpopulation abnormalities. IgA-deficient patients may progress to panhypogammaglobulinemia characteristic of CVID. Selective IgA and CVID are found in the same family.

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.

The signs and symptoms of "activated PI3K Delta Syndrome" are consistent with the following:

- Immunodeficiency

- Lymphadenopathy

- Sinopulmonary infections

- Bronchiectasis