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.

The basic tests performed when an immunodeficiency is suspected should include a full blood count (including accurate lymphocyte and granulocyte counts) and immunoglobulin levels (the three most important types of antibodies: IgG, IgA and IgM).

Other tests are performed depending on the suspected disorder:

- Quantification of the different types of mononuclear cells in the blood (i.e. lymphocytes and monocytes): different groups of T lymphocytes (dependent on their cell surface markers, e.g. CD4+, CD8+, CD3+, TCRαβ and TCRγδ), groups of B lymphocytes (CD19, CD20, CD21 and Immunoglobulin), natural killer cells and monocytes (CD15+), as well as activation markers (HLA-DR, CD25, CD80 (B cells).

- Tests for T cell function: skin tests for delayed-type hypersensitivity, cell responses to mitogens and allogeneic cells, cytokine production by cells

- Tests for B cell function: antibodies to routine immunisations and commonly acquired infections, quantification of IgG subclasses

- Tests for phagocyte function: reduction of nitro blue tetrazolium chloride, assays of chemotaxis, bactericidal activity.

Due to the rarity of many primary immunodeficiencies, many of the above tests are highly specialised and tend to be performed in research laboratories.

Criteria for diagnosis were agreed in 1999. For instance, an antibody deficiency can be diagnosed in the presence of low immunoglobulins, recurrent infections and failure of the development of antibodies on exposure to antigens. The 1999 criteria also distinguish between "definitive", "probable" and "possible" in the diagnosis of primary immunodeficiency. "Definitive" diagnosis is made when it is likely that in 20 years, the patient has a >98% chance of the same diagnosis being made; this level of diagnosis is achievable with the detection of a genetic mutation or very specific circumstantial abnormalities. "Probable" diagnosis is made when no genetic diagnosis can be made, but the patient has all other characteristics of a particular disease; the chance of the same diagnosis being made 20 years later is estimated to be 85-97%. Finally, a "possible" diagnosis is made when the patient has only some of the characteristics of a disease are present, but not all.

The following symptoms (signs) are consistent with complement deficiency in general:

Acquired hypocomplementemia may occur in the setting of bone infections (osteomyelitis), infection of the lining of the heart (endocarditis), and cryoglobulinemia. Systemic lupus erythematosus is associated with low C3 and C4 Membranoproliferative glomerulonephritis usually has low C3.

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.

The bare lymphocyte syndrome, type II (BLS II) is a rare recessive genetic condition in which a group of genes called major histocompatibility complex class II (MHC class II) are not expressed.

The result is that the immune system is severely compromised and cannot effectively fight infection. Clinically, this is similar to severe combined immunodeficiency (SCID), in which lymphocyte precursor cells are improperly formed. As a notable contrast, however, bare lymphocyte syndrome does not result in decreased B- and T-cell counts, as the development of these cells is not impaired.

Diarrhea can be among the associated conditions.

The main sign of the disease is life-threatening, recurrent bacterial or fungal soft tissue infections. These infections are often apparent at birth and may spread throughout the body. Omphalitis (infection of the umbilical cord stump) is common shortly after birth. Other signs include delayed separation of the umbilical cord, periodontal disease, elevated neutrophils, and impaired wound healing, but not increased vulnerability to viral infections or cancer. Such patients have fever as the manifestation of infection, inflammatory responses are indolent.

Leukocyte adhesion deficiency-1 (LAD1) is a rare and often fatal genetic disorder in humans.

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.

Bare lymphocyte syndrome is a condition caused by mutations in certain genes of the major histocompatibility complex or involved with the processing and presentation of MHC molecules. It is a form of severe combined immunodeficiency.

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).

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

It is a type of immunoproliferative disorder.

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.

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.

Clinically, PASLI disease is characterized by recurrent sinopulmonary infections that can lead to progressive airway damage. Patients also suffer from lymphoproliferation (large lymph nodes and spleen), chronic viremia due to EBV or CMV, distinctive lymphoid nodules at mucosal surfaces, autoimmune cytopenias, and EBV-driven B cell lymphoma. Importantly, the clinical presentations and disease courses are variable with some individuals severely affected, whereas others show little manifestation of disease. This “variable expressivity,” even within the same family, can be striking and may be explained by differences in lifestyle, exposure to pathogens, treatment efficacy, or other genetic modifiers.

The symptoms are very similar to graft-versus-host disease (GVHD). This is because the patients have some T cells with limited levels of recombination with the mutant RAG genes. These T cells are abnormal and have a very specific affinity for self antigens found in the thymus and in the periphery. Therefore, these T cells are auto-reactive and cause the GVHD phenotype.

A characteristic symptom is chronic inflammation of the skin, which appears as a red rash (early onset erythroderma). Other symptoms include eosinophilia, failure to thrive, swollen lymph nodes, swollen spleen, diarrhea, enlarged liver, low immunoglobulin levels (except immunoglobulin E, which is elevated), low T cell levels, and no B cells.

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 .

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.

Complement 3 deficiency is a genetic condition affecting complement component 3.

It can cause systemic lupus erythematosus-like symptoms.

It can lead to an increase in pyogenic infections from encapsulated bacteria.

Individuals with BENTA disease have polyclonal B cell lymphocytosis (i.e. excess B cells) developing in infancy, in addition to splenomegaly and lymphadenopathy. Patients may have low serum IgM and mildly anergic T cells. These features likely contribute to the mild immunodeficiency seen with BENTA disease. Patients are generally susceptible to recurrent sinopulmonary and ear infections in childhood, and may be more susceptible to certain viruses including Epstein-Barr virus, BK virus, and molluscum contagiosum.

PASLI disease is a rare genetic disorder of the immune system. PASLI stands for “p110 delta activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency.” The immunodeficiency manifests as recurrent infections usually starting in childhood. These include bacterial infections of the respiratory system and chronic viremia due to Epstein-Barr virus (EBV) and/or cytomegalovirus (CMV). Individuals with PASLI disease also have an increased risk of EBV-associated lymphoma. Investigators Carrie Lucas, Michael Lenardo, and Gulbu Uzel at the National Institute of Allergy and Infectious Diseases at the U.S. National Institutes of Health and Sergey Nejentsev at the University of Cambridge, UK simultaneously described a mutation causing this condition which they called Activated PI3K Delta Syndrome (APDS).

The severe combined immunodeficiency (SCID) is a severe immunodeficiency genetic disorder that is characterized by the complete inability of the adaptive immune system to mount, coordinate, and sustain an appropriate immune response, usually due to absent or atypical T and B lymphocytes. In humans, SCID is colloquially known as "bubble boy" disease, as victims may require complete clinical isolation to prevent lethal infection from environmental microbes.

Several forms of SCID occur in animal species. Not all forms of SCID have the same cause; different genes and modes of inheritance have been implicated in different species.

Atypical infections are the key clinical manifestation of SGD. Within the first few years of life, patients will experience repeated pyogenic infections by species such as "Staphylococcus aureus", "Pseudomonas aeruginosa" or other Enterobacteriaceae, and "Candida albicans". Cutaneous ulcers or abscesses and pneumonia and chronic lung disease are common. Patients may also develop sepsis, mastoiditis, otitis media, and lymphadenopathy. Infants may present with vomiting, diarrhea, and failure to thrive.

Diagnosis can be made based upon CEBPE gene mutation or a pathognomonic finding of a blood smear showing lack of specific granules. Neutrophils and eosinophils will contain hyposegmented nuclei (a pseudo-Pelger–Huet anomaly).

According to a European registry study, the mean age at onset of symptoms was 26.3 years old. As per the criteria laid out by ESID (European Society for Immunodeficiencies) and PAGID (Pan-American Group for Immunodeficiency), CVID is diagnosed if:

- the person presents with a marked decrease of serum IgG levels (<4.5 g/L) and a marked decrease below the lower limit of normal for age in at least one of the isotypes IgM or IgA;

- the person is four years of age or older;

- the person lacks antibody immune response to protein antigens or immunization.

Diagnosis is chiefly by exclusion, i.e. alternative causes of hypogammaglobulinemia, such as X-linked agammaglobulinemia, must be excluded before a diagnosis of CVID can be made.

Diagnosis is difficult because of the diversity of phenotypes seen in people with CVID. For example, serum immunoglobulin levels in people with CVID vary greatly. Generally, people can be grouped as follows: no immunoglobulin production, immunoglobulin (Ig) M production only, or both normal IgM and IgG production. Additionally, B cell numbers are also highly variable. 12% of people have no detectable B cells, 12% have reduced B cells, and 54% are within the normal range. In general, people with CVID display higher frequencies of naive B cells and lower frequencies of class-switched memory B cells. Frequencies of other B cell populations, such as IgD memory B cells, transitional B cells, and CD21 B cells, are also affected, and are associated with specific disease features. Although CVID is often thought of as a serum immunoglobulin and B cell-mediated disease, T cells can display abnormal behavior. Affected individuals typically present with low frequencies of CD4, a T-cell marker, and decreased circulation of regulatory T cells and iNKT cell. Notably, approximately 10% of people display CD4 T cell counts lower than 200 cells/mm; this particular phenotype of CVID has been named LOCID (Late Onset Combined Immunodeficiency), and has a poorer prognosis than classical CVID.

XMEN disease is a rare genetic disorder of the immune system that illustrates the role of Mg2+ in cell signaling. XMEN stands for “X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection, and neoplasia.” It is characterized by CD4 lymphopenia, severe chronic viral infections, and defective T-lymphocyte activation. Investigators in the laboratory of Dr. Michael Lenardo, National Institute of Allergy and Infectious Diseases at the National Institutes of Health first described this condition in 2011.